Topical oil-in-water emulsions containing retinoids

ABSTRACT

Skin care compositions comprising an oil-in-water emulsion base containing retinoids and possessing good physical and chemical stability. More particularly, said skin care compositions contain (a) an emulsifier system selected from the group consisting of: (i) a mixture of glyceryl stearate and polyethylene glycol 100 stearate; (ii) cetearyl alcohol and cetearyl glucoside; (iii) a mixture of a polyethylene glycol ethers of stearyl alcohol; and (iv) a mixture of sorbitan stearate and polysorbate 60; (b) a co-emulsifier selected from the group consisting of cetyl alcohol, stearyl alcohol and mixtures thereof; (c) an oil phase present in the amount of from about 5 to about 20 percent by weight of the total emulsion composition which contains (i) a light, dry absorbable oil and (ii) substantive, emollient oils or waxes, wherein the light, dry absorbable oil and the substantive oil or wax are present in a ratio of from about 1:3 for about 10:1.

This application hereby incorporates by reference U.S. patentapplication Ser. No. 08/523,836 filed Sep. 6, 1995 and Japanese PatentApplication No. Hei 6-238639, filed Sep. 7, 1994 and from which thisapplication claims the benefit of priority.

FIELD OF THE INVENTION

This invention relates to skin care compositions which may containretinoids and other ingredients which generally improve the quality ofthe skin, particularly human facial skin. More particularly, the presentinvention relates to chemically stable skin care compositions comprisingan oil-in-water emulsion and certain retinoids and to methods for makingsuch compositions. This invention also relates to packaging and methodsof packaging such compositions so as to preserve their chemicalstability.

BACKGROUND OF THE INVENTION

Skin care compositions containing retinoids have become the focus ofgreat interest in recent years. Retinoic acid, also known as Vitamin Aacid or tretinoin, is well-known for the treatment of such skinconditions as acne and products containing retinoic acid arecommercially available in various forms from the Dermatological Divisionof Ortho Pharmaceutical Corporation. Such products, for example, includeRetin A* creams, an oil-in-water emulsion of retinoic acid containing asan oil-soluble antioxidant, butylated hydroxytoluene (BHT); Retin A*liquid, a solution of retinoic acid in a polyethylene glycol/ethanolsolvent employing BHT as an antioxidant; and Retin A* gel, whichcomprises retinoic acid in a gel vehicle comprising ethyl alcohol as thesolvent, hydroxypropyl cellulose as the thickener or gelling agent andBHT as an antioxidant. These retinoic acid containing products haveproven stable and capable of providing active ingredients after extendedperiods of storage.

More recently, however, wider use of retinoids has been suggested fortreatments other than acne such as, for example, the treatment of skinagainst photoaging and sun damage. Many individuals who have had a gooddeal of sun exposure in childhood will show the following grosscutaneous alterations in later adult life: wrinkling, leatheriness,yellowing, looseness, roughness, dryness, mottling (hyperpigmentation)and various premalignant growths (often subclinical). These changes aremost prominent in light-skinned persons who burn easily and tan poorly.These cumulative effects of sunlight are often referred to as"photoaging". Although the anatomical degradation of the skin is mostadvanced in the elderly, the destructive effects of excessive sunexposure are already evident by the second decade. Serious microscopicalterations of the epidermis and dermis occur decades before thesebecome clinically visible. Wrinkling, yellowing, leatheriness and lossof elasticity are very late changes.

The problem of skin aging is addressed in U.S. Pat. No. 4,603,146,wherein Vitamin A acid in an emollient vehicle is suggested as atreatment. Further, in U.S. Pat. No. 4,877,805, it is suggested that anumber of retinoids are useful for restoring and reversing sun damage ofhuman skin.

When considering the use of retinoids in skin care products, it isbelieved that certain retinoids such as, for example, retinol (Vitamin Aalcohol), retinal (Vitamin A aldehyde) and retinyl esters such asretinyl acetate and retinyl palmitate would be preferred over retinoicacid. This is because they are endogenous compounds naturally occurringin the human body and essential for good growth, differentiation of theepithelial tissues and reproduction. Additionally, excess retinol isstored in the human body largely in an inactive ester form, e.g.,retinyl palmitate and, to some extent, retinyl acetate. The aldehyde,retinal, also a preferred form, is an active metabolite of retinol.Accordingly, attention has turned toward formulating skin carecompositions which contain these preferred, naturally occurringretinoids.

In formulating products containing such retinoids, the same propertiessought with respect to the retinoic acid formulas are desirable forother retinoid containing compositions. Specifically, much attention isdirected toward providing a composition which is aesthetically pleasingand which can deliver active ingredients after a substantial shelf life.Not surprising, in formulating products containing such retinoids, theart is led to the experience gained in the already existing formulascontaining retinoic acid. Typically, such formulas comprise oil-in-wateremulsions wherein the retinoic acid is carried within the oil phase andis protected from oxidation by employing an oil-soluble antioxidant.With respect to the form of the emulsion, oil-in-water emulsions havebeen preferred in that, as compared to water-in-oil emulsions forexample, they are non-occlusive, non-greasy, compatible with other suchemulsion products, easy to remove from the skin and are regarded as moreaesthetically pleasing as well as being more economical to manufacture.With respect to chemical stability of the active ingredient, it has beenexperienced that the retinoic acid in the oil phase is, in the main,well protected by including in such oil phase an oil solubleantioxidant.

Thus, various oil-in-water emulsions containing retinoic acid and BHT,as oil-soluble antioxidant have been described and sold, for example, inU.S. Pat. No. 3,906,108, U.S. Pat. No. 4,66,805, and U.S. Pat. No.4,247,547. The retinoic acid containing compositions described in thesepatents have proven to be, or are said to be, chemically stable.Therefore, a number of skin care products have appeared in themarketplace incorporating other retinoids, including, for example,retinol, retinal and retinyl esters such as retinyl acetate and retinylpalmitate, and these unsurprisingly emulate the formulas of thecommercial retinoic acid compositions, i.e., are oil-in-water emulsionsprotected by oil-soluble antioxidants. Unfortunately, it has been foundthat these other retinoids in such compositions quickly lose theiractivity and either oxidize or isomerize to non-efficacious chemicalforms with the result that the amount of retinoid actually available toprovide the beneficial effects of the product is reduced, in anunacceptably short period of time, to an ineffective quantity andeventually to only trace quantities.

There have been attempts to formulate a stable composition comprisingretinol, retinal, retinyl acetate and retinyl palmitate in oil-in-wateremulsions, such as in U.S. Pat. No. 4,826,828. Avon Products, Inc., theassignee of U.S. Pat. No. 4,826,828, sells two skin care products calledBioadvance and Bioadvance 2000. Each of these products is supplied intwo bottles, portions of which are mixed together just prior to use.U.S. Pat. No. 4,720,353 (Bell) describes water-in-oil emulsion carriersfor various medicaments and drugs intended for topical application tothe skin. Other water-in-oil type emulsions have been described in EP 0343 444 A2 (Siemer et al.) and EP 0 330 496 A2 (Batt).

Clum et al., in U.S. patent application Ser. No. 07/719,264, nowabandoned, describe stable water-in-oil compositions containing aretinoid and a stabilizing system selected from the group consisting of:(a) a chelating agent and at least one oil-soluble antioxidant; (b) achelating agent and at least one water-soluble antioxidant; and (c) anantioxidant present in each of the oil and water phases of the emulsion.This composition retains at least about 60% of the retinoids after 13weeks of storage at 40° C. Although this system is quite stable anduseful in retinoid-containing products, it is nevertheless awater-in-oil emulsion and retains all the attributes, advantages anddisadvantages of such a formulation. It is therefore an object of thisinvention to provide an oil-in-water formulation which is stable andacceptable for use on the skin.

SUMMARY OF THE INVENTION

In accordance with the present invention, it has now been unexpectedlyfound that certain retinoids may be successfully stabilized againstchemical degradation by incorporating them into oil-in-water emulsionscomprising a specifically defined stabilizing system. In addition, thisinvention relates to oil-in-water emulsion compositions which arecosmetically elegant.

The retinoids which can be stabilized against chemical degradation inaccordance with the principles of the present invention are retinol(Vitamin A alcohol), retinal (Vitamin A aldehyde), retinyl acetate,retinyl palmitate and mixtures thereof. It is also theorized that otherretinoids, including synthetic retinoids and retinoid-like chemicals maybenefit from inclusion in the formulations of this invention.

As used herein, the "chemical stability" or "stability" of a retinoid isdefined in terms of the percentage of the specified retinoid which isretained in its original chemical form after the composition has beenstored for a specified period of time at a specified temperature. Thus,if the original concentration of all-trans retinol in an absoluteethanol solution were 0.20% by weight and, after two (2) weeks' storageat room temperature (21° C.±1° C.), the concentration of all-transretinol were 0.18% by weight, then the original solution would becharacterized as having a chemical stability of 90% after two weeks'storage at room temperature. In the same fashion, if an emulsioncomprising all-trans retinol had an initial concentration of 0.30% byweight and after storage for 13 weeks at 40° C. had a concentration ofall trans-retinol of 0.24% by weight, then the original emulsion retinolof 80% after 13 weeks storage at 40° C.

Specifically, a commercially usable composition should exhibit astability of at least about 60% of the active retinoid(s) after 13 weeksstorage at 40° C. Preferably, the compositions of this invention exhibita stability of at least about 70% after 13 weeks' storage at 40° C.

Accordingly, there is provided, in accordance with the teachings of thisinvention, a skin care composition comprising an oil-in-water emulsionand a retinoid selected from the group consisting of retinol, retinal,retinyl acetate, retinyl palmitate and mixtures thereof, saidcomposition having a pH of between about 4 and about 10; saidcomposition further comprising an oil phase, said oil phase having arelatively low level of unsaturation; said composition furthercomprising a stabilizing system selected from the group consisting of:

a) at least one oil-soluble antioxidant;

b) a chelating agent and at least one oil-soluble antioxidant;

c) a chelating agent; and

d) a chelating agent and an antioxidant present in each of the oil andwater phases of said emulsion;

said composition retaining at least about 70% of said retinoids after 13weeks' storage at 40° C.

Additionally, there are provided herein oil-in-water emulsions havingnovel emulsification systems. The oil-in-water emulsion compositions ofthis invention preferably contain:

a) an emulsifier system selected from the group consisting of:

i) a mixture of glyceryl stearate and polyethylene glycol 100 stearate;

ii) cetearyl alcohol and cetearyl glucoside;

iii) a mixture of a polyethylene glycol ether of stearyl alcohol of theformula:

    CH.sub.3 (CH.sub.2).sub.16 CH.sub.2 (OCH.sub.2 CH.sub.2).sub.n OH

wherein n is 21 and a polyethylene glycol ether of stearyl alcohol ofthe formula:

    CH.sub.3 (CH.sub.2).sub.16 CH.sub.2 (OCH.sub.2 CH.sub.2).sub.n OH

wherein n is 2; and

iv) a mixture of sorbitan stearate and polysorbate 60 (a mixture ofstearate esters of sorbitol and sorbitol anhydrides condensed with 20moles of ethylene oxide);

b) a co-emulsifier selected from the group consisting of: cetyl alcohol,stearyl alcohol and mixtures thereof;

c) an oil phase present in the amount of from about 2 to about 20percent by weight of the total emulsion composition comprising:

i) a light, dry absorbable oil and

ii) substantive, emollient oils or waxes

wherein such dry absorbable oil and such substantive emollient oil arepresent in a ratio of from about 1:3 to about 10:1.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

As described above, the composition of the invention is in the form of aparticular type of emulsion, namely oil-in-water. As used herein, thegenerally accepted concept of an emulsion applies, i.e., an intimatemixture of two immiscible liquids which remains unseparated for anacceptable shelf life at or about room temperature. Ordinarily, when twoimmiscible liquids are mechanically agitated, both phases initially tendto form droplets. Thereafter, when the agitation ceases, the dropletsquickly coalesce, and the two liquids tend to separate. On the otherhand, an emulsion may be formed and physically stabilized and thelifetime of the droplets in intimate mixture materially increased if acompound, referred to as an emulsifier, is added to the immiscibleliquids. Usually only one phase persists in droplet form for a prolongedperiod of time, and this is referred to as the internal phase which issurrounded by an external phase. An oil-in-water emulsion is one inwhich the external phase (also called the continuous phase) compriseswater or an aqueous solution and the internal phase (also called thediscontinuous or disperse phase) comprises an oil or mixture of mutuallysoluble oils.

A suitable vehicle for delivery of skin care active ingredients shouldcombine a variety of features. It should be esthetically acceptable forits intended use, i.e. it should be compatible with other productsincluding color cosmetics, it should be low or lacking in odor, easy toapply and spread, quickly absorbed and should leave a non-greasy butperceptibly functional residue. It should also be easily and quicklyproduced, cost-effective and have suitable physical stability under avariety of adverse conditions, such as high and low temperatures. Itshould also have a relatively long shelf life under normal commercialand residential environmental conditions.

The novel compositions of this invention should contain an estheticallyacceptable oil phase composed of non-volatile compounds which remain onthe skin after application. They should also contain an acceptableemulsification system which assists in maintaining the physicalstability of the formulation. Surprisingly, the emulsification systemsof this invention have been found to act to "balance" the estheticappearance and feel of the compositions while maintaining the physicalstability of the compositions.

The emulsifiers useful in the compositions of this invention may bechosen from the following: (i) a mixture of glyceryl stearate andpolyethylene glycol 100 stearate (available commercially as Arlacel 165from ICI Americas); (ii) cetearyl alcohol and cetearyl glucoside(preferably in combination with cetearyl alcohol), availablecommercially as Montanov 68 from SEPPIC; (iii) a mixture of apolyethylene glycol ether of stearyl alcohol of the formula:

    CH.sub.3 (CH.sub.2).sub.16 CH.sub.2 (OCH.sub.2 CH.sub.2).sub.n OH

wherein n is 21 and a polyethylene glycol ether of stearyl alcohol ofthe formula:

    CH.sub.3 (CH.sub.2).sub.16 CH.sub.2 (OCH.sub.2 CH.sub.2).sub.n OH

wherein n is 2 (available commercially as Brij 721 and Brij 72 from ICIAmericas); and (iv) a mixture of sorbitan stearate and polysorbate 60 (amixture of stearate esters of sorbitol and sorbitol anhydrides condensedwith 20 moles of ethylene oxide), available commercially as,respectively, Span 60 and Tween 60 from ICI Americas.

Two particularly preferred emulsification systems include (a) a mixtureof glyceryl stearate and polyethylene glycol 100 stearate and (b)cetearyl alcohol and cetearyl glucoside. These emulsification systemspermit the water and oil phases to be combined such that the oil phaseforms droplets in the water phase. When incorporating system (a) into acomposition of this invention, the ratio of glyceryl stearate topolyethylene glycol 100 stearate should be from about 1:1. Whenincorporating system (b) into a composition of this invention, the ratioof cetearyl alcohol to cetearyl glucoside should be from about 6:1 toabout 3:1. The amount of emulsifier present in the compositions of thisinvention should be from about 1 to about 10 weight percent. Morepreferably, from about 1 to about 6 weight percent should be used. Mostpreferably, from about 1 to about 5 weight percent should be used.

In order to maintain the droplets as separate entities, and to preventthe phases from separating, accessory emulsifiers or "co-emulsifiers"are often utilized. These co-emulsifiers prevent the oil phase fromcoalescing or creaming and keep the phases physically stable as anemulsion prior to application to the skin. They lend "body" to theemulsion and give the formulation its character as a lotion or a creamby imparting viscosity to the composition. It has been found thatparticularly useful co-emulsifiers are fatty alcohols such as cetyl andstearyl alcohols and the like. Preferably, a mixture of cetyl andstearyl alcohols should be used as the co-emulsifier in most cases.Preferably, the ratio of cetyl alcohol to stearyl alcohol should be fromabout 2:1 to about 1:2. Preferably, the co-emulsifier should composefrom about 1 to about 5 weight percent of the composition. The preferredratio of emulsifier to co-emulsifier is from about 3:1 to about 1:10.More preferably, the ratio should be from about 3:1 to about 1:3.

The present invention also provides oil-in-water emulsion compositionscontaining at least one retinoid compound wherein the physical stabilityof the emulsion and the chemical stability of the active ingredients areexcellent. The present invention also provides a method for making suchemulsion compositions and a method and apparatus for storing suchemulsion compositions in order to maintain their stability duringstorage and prior to use by the consumer. It should be noted, however,that the base emulsion, including the emulsifiers, co-emulsifiers andoil phase, of this invention may be used not only in combination withretinoids, but with a variety of active topical ingredients with orwithout the inclusion of retinoid materials.

The skin care compositions of the present invention comprising anoil-in-water emulsion can be in the format of cream or lotionformulations, as desired, by varying the relative quantities of the oiland water phases of the emulsion. The pH of the compositions should bein the range of from about 4 to about 10; preferably they should be fromabout 6 to about 8. It has been found that, in compositions having a pHof about 6 or more, the retinoid is more stable than at pH of less than6. Furthermore, the stability of the retinol is less dependent upon theactual materials used in the formulation at pH of 6 or more.

Preferably, the oils used in the compositions of this invention arerelatively highly saturated, preferably those having a relatively lowiodine value. The contribution to unsaturation, density C, of anindividual oil in the composition is calculated as follows:

    C=A×B,

where A is the percentage of the unsaturated oil or fat used in anoil-in-water emulsion and B is the iodine value of the unsaturated oil.If a mixture of oils is used in the oil phase, the total unsaturationdensity will be the sum of all individual C values. Accordingly, an oilphase having an unsaturation density or total C of 1200 or less andpreferably 500 or less should be used in the formulations of thisinvention. It is theorized that saturated oils and/or fats are lessreactive than unsaturated oils and fats, due to the presence of reactivedouble bonds in unsaturated oils and fats, which can initiate reactionswith the retinoids and other materials in the compositions of thisinvention. Synthetic oils that are useful are fatty acid esters, fattyalcohols, for example, octyl hydroxystearate, cetyl palmitate, cetylalcohol, glyceryl stearate and PEG-100 stearate, stearyl alcohol, octylpelargonate and the like. Examples of preferred oils are as follows:Finsolv TN (available from Finetex of New Jersey), Miglyol 812(available from Huls Corporation of New York), silicone oil (Dow Corningof Michigan), mineral oil, and the like, having very low iodine valuesare also quite useful in the compositions of this invention.Furthermore, the percentage of the oil present in the compositions ofthis invention is also relevant: the lower the percentage of high-iodinevalue oil, the more stable the retinoid in the composition.

When the emulsion compositions of this invention are applied to theskin, the aqueous portions of the compositions volatilize, while thenon-volatile portion of the compositions of this invention remain uponthe skin. The oil phase components along with the co-emulsifiers andemulsifiers make up this non-volatile portion of the compositions. Thus,the esthetics of the non-volatile portion are quite important in makingthe compositions of this invention.

It is desirable to compose an oil phase containing both at least one"dry" absorbable emollient oil and at least one substantive oil or wax.A dry absorbable emollient oil is needed for the purpose of quicklyabsorbing the composition into the skin. This dry absorbable emollientoil is generally not greasy, a desirable attribute. However, thisattribute can be unpleasant if the dry absorbable oil is the only oil inthe oil phase. Because such an oil is easily absorbed, it leaves nopositive "feel" on the skin. Therefore, it should be balanced with oneor more substantive skin conditioning oils or waxes, which are soothingand coat the skin, leaving an "afterfeel" perceptible to the user. Thesesubstantive oils and waxes have these desirable traits, but, when usedin excess, can leave a greasy feeling on the skin. Thus, the benefit ofthe emulsion base of this invention is that it balances the esthetics ofthe compositions with respect to the oil phase and has the capability ofrebalancing it with respect to other ingredients which may provideactive skin conditioning and/or therapeutic benefits. Preferably, theratio of dry absorbable emollient oil to substantive skin conditioningoils is from about 1:3 to about 10:1. More preferably, the ratio is fromabout 1:3 to about 5:1. Most preferably, the ratio should be about 1:1.The dry absorbable emollient is most preferably C12-15 alkyl benzoate(commercially available as Finsolv TN from Finetex), capric-caprylictriglycerides (commercially available from Huls as Miglyol 812) or othersuitable synthetic triglycerides known to those of skill in the art.Substantive oils or waxes may be selected from white petrolatum, octylhydroxystearate, cetyl palmitate and the like. The total amount of oilphase may vary from a very low level, e.g., about 2% of the overallcomposition, to as much as about 20% of the composition. Morepreferably, the oil phase should be composed of from about 5 to about12% of the composition in order to provide the desired spreadability andconsistency without leaving excessive residue with the perception ofgreasiness and oily coating on the skin. Variations within this rangemay depend upon the characteristics of the additional components,including vitamins, sunscreens and the like, both to serve as a vehicleto apply the active ingredients properly to the skin and to modify thesometimes undesirable esthetics contributions from these components.

In addition to such oils, other emollients and surface active agentshave been incorporated in the emulsions, including glycerol trioleate,acetylated sucrose distearate, sorbitan trioleate, polyoxyethylene (1)monostearate, glycerol monooleate, sucrose distearate, polyethyleneglycol (50) monostearate, octylphenoxypoly (ethyleneoxy) ethanol,decaglycerin penta-isostearate, sorbitan sesquioleate, hydroxylatedlanolin, lanolin, triglyceryl diisostearate, polyoxyethylene (2) oleylether, calcium stearoyl-2-lactylate, methyl glucoside sesquistearate,sorbitan monopalmitate, methoxy polyethylene glycol-22/dodecyl glycolcopolymer (Elfacos E200), polyethylene glycol-45/dodecyl glycolcopolymer (Elfacos ST9), polyethylene glycol 400 distearate, and lanolinderived sterol extracts, glycol stearate and glycerol stearate;alcohols, such as cetyl alcohol and lanolin alcohol; myristates, such asisopropyl myristate; cetyl palmitate; cholesterol; stearic acid;propylene glycol; glycerine, sorbitol and the like.

It is also preferable to have at least one oil-soluble antioxidant inthe compositions of this invention. The oil-soluble antioxidants whichare useful in the compositions of the present invention includebutylated hydroxytoluene (BHT), ascorbyl palmitate, butylatedhydroxanisole (BHA), phenyl-α-naphthylamine, hydroquinone, propylgallate, nordihydroguaiaretic acid, rosemary extract and mixturesthereof as well as any other known oil-soluble antioxidant compatiblewith the other components of the compositions.

Preferably, a water-soluble antioxidant should be present in the waterphase of the compositions of this invention. The water-solubleantioxidants which are useful in the compositions of this inventioninclude ascorbic acid, sodium metabisulfite, sodium bisulfite, sodiumthiosulfite, sodium formaldehyde sulfoxylate, isoascorbic acid,thioglyerol, thiosorbitol, thiourea, thioglycolic acid, cysteinehydrochloride, 1,4-diazobicyclo-(2,2,2)-octane, malic acid, fumaricacid, licopene and mixtures thereof as well as any other knownwater-soluble antioxidant compatible with the other components of thecompositions.

The composition of this invention can contain additives, as required,such as a humectant, an antioxidant, a preservative, a flavor,fragrances, a surface active agent, a binder, and the like, as well asskin protectant agents, therapeutic agents and "cosmeceuticals".

Preferably, a detackifying material should be incorporated into thecompositions of this invention. When emulsions are applied to the skin,they break apart. Often, they leave a sticky feeling as they dry beforethe emulsion has totally broken and been absorbed into the skin. This isparticularly true of emulsions containing cetyl and stearyl alcohols,due to the liquid crystal nature of these materials, as they are quiteslow to give up water upon application to the skin. Unexpectedly, it hasbeen found that certain detackifying materials may be added to thecompositions of this invention in order to combat this stickiness.Materials having a "talc-like" character, i.e., which crystallize into aplate-like form, are preferable for use as they add lubricity to thecompositions of this invention. Other non-platey solids, although lesspreferably, are also acceptable for use as a detackifier. Preferably,the detackifying material used in the compositions of this inventionshould be lauroyl lysine, titanium dioxide, zinc oxide, pulverizednylon, oatmeal and surface treated oatmeal, silica, mica, bariumsulfate, aluminum starch, octenyl succinate, micronized polyethylene,boron nitride, corn starch, talc or silicone waxes or oils and otherinsoluble particles which do not leave visual residue on the skin. Morepreferably, the detackifying material should be lauroyl lysine, boronnitride, mica and talc. Most preferably, the detackifier should belauroyl lysine (such as Amihope LL commercially available fromAjinomoto). Preferably, the detackifier is present at very lowconcentrations, i.e., from about 0.01 to about 7% by weight. Morepreferably, it should be present at the amount of from about 0.5 toabout 1% by weight. Other detackifying materials which are compatiblewith fatty emulsions would also be appropriate for use in thecompositions of this invention.

Surprisingly, it has also been found that small concentrations of loweralkyl alcohols also contribute an esthetically benefit to thecompositions of this invention. It has been found that the addition oflower alkyl solvent alcohols mitigate the waxy feel of the emulsions onthe skin due to the presence of cetyl and stearyl alcohols. It isbelieved that lower alkyl alcohols assist in solubilizing the liquidcrystal structures formed by these fatty alcohols. Preferably, loweralkyl alcohols having from one to four carbon atoms are useful in thecompositions of this invention. Most preferably, ethyl alcohol should bepresent in the compositions of this invention. Preferably, they shouldbe present in an amount of from about 2 to about 10% by weight of thecompositions.

Examples of the humectant include glycerol, sorbitol, propylene glycol,ethylene glycol, 1,3-butylene glycol, polypropylene glycol, xylitol,maltitol, lactitol and the like. They may be used either singly or incombination.

Examples of the preservatives include salicylic acid, chlorhexidinehydrochloride, phenoxyethanol, sodium benzoate, methylpara-hydroxybenzoate, ethyl para-hydroxybenzoate, propylpara-hydroxybenzoate, butyl para-hydroxybenzoate and the like.

Examples of the flavor and fragrance include menthol, anethole, carvone,eugenol, limonene, ocimene, n-decylalcohol, citronellol, a-terpineol,methyl salicylate, methyl acetate, citronellyl acetate, cineole,linalool, ethyl linalool, vanillin, thymol, spearmint oil, peppermintoil, lemon oil, orange oil, sage oil, rosemary oil, cinnamon oil,pimento oil, cinnamon leaf oil, perilla oil, wintergreen oil, clove oil,eucalyptus oil and the like.

Examples of surface active agents include sodium alkyl sulfates, e.g.,sodium lauryl sulfate and sodium myristyl sulfate, sodium N-acylsarcosinates, e.g., sodium N-lauroyl sarcosinate and sodium N-myristoylsarcosinate, sodium dodecylbenzenesulfonate, sodium hydrogenated coconutfatty acid monoglyceride sulfate, sodium lauryl sulfoacetate and N-acylglutamates, e.g., N-palmitoyl glutamate, N-methylacyltaurin sodium salt,N-methylacylalanine sodium salt, sodium a-olefin sulfonate and sodiumdioctylsulfosuccinate; N-alkylaminoglycerols, e.g.,N-lauryldiaminoethylglycerol and N-myristyldiaminoethylglycerol,N-alkyl-N-carboxymethylammonium betaine and sodium2-alkyl-1-hydroxyethylimidazoline betaine; polyoxyethylenealkyl ether,polyoxyethylenealkylaryl ether, polyoxyethylenelanolin alcohol,polyoxyethyleneglyceryl monoaliphatic acid ester,polyoxyethylenesorbitol aliphatic acid ester, polyoxyethylene aliphaticacid ester, higher aliphatic acid glycerol ester, sorbitan aliphaticacid ester, Pluronic type surface active agent, andpolyoxyethylenesorbitan aliphatic acid esters such aspolyoxyethylenesorbitan monooleate and polyoxyethylenesorbitanmonolaurate. Emulsifier-type surfactants known to those of skill in theart should be used in the compositions of this invention.

Examples of the binder or thickener include cellulose derivatives suchas alkali metal salts of carboxymethylcellulose, methyl cellulose,hydroxyethyl cellulose and sodium carboxymethylhydroxyethyl cellulose,alkali metal alginates such as sodium alginate, propylene glycolalginate, gums such as carrageenan, xanthan gum, tragacanth gum, carayagum and gum arabic, and synthetic binders such as polyvinyl alcohol,polysodium acrylate and polyvinyl pyrrolidone.

Thickeners such as natural gums and synthetic polymers, as well aspreservatives such as methylparaben, butyl paraben, propylparaben andphenoxyethanol, coloring agents and fragrances also are commonlyincluded in such compositions.

The antioxidants should be utilized in a stabilizing effective amountand may range in total from about 0.001 to 5% based on the weight of thetotal composition, preferably from about 0.01 to about 1%. The amount ofantioxidants utilized in the compositions of the present invention isdependent in part on the specific antioxidants selected, the amount ofand specific retinoid being protected and the processing conditions.

In certain aspects of this invention, the compositions should include achelating agent. The retinoid compounds of this invention are sensitiveto metal ions and in particular to bi- and tri-valent cations and incertain instances, appear to degrade rapidly in their presence. Thechelating agent forms a complex with the metal ions thereby inactivatingthem and preventing them from affecting the retinoid compounds.Chelating agents which are useful in the compositions of the presentinvention include ethylenediamine tetra acetic acid (EDTA) andderivatives and salts thereof, dihydroxyethyl glycine, citric acid,tartaric acid, and mixtures thereof. The chelating agents should beutilized in a stabilizing effective amount and may range from about 0.01to about 2% based on the weight of the total composition, preferablyfrom about 0.05 to about 1%. Most preferably, the chelating agent shouldbe EDTA.

The retinoid compounds which are useful in the compositions of thepresent invention consist of Vitamin A alcohol (retinol), Vitamin Aaldehyde (retinal) and Vitamin A esters (retinyl acetate and retinylpalmitate), although other retinoids may be incorporated into theemulsion compositions of this invention. These retinoids are utilized inthe compositions of the present invention in a therapeutically effectiveamount that may range from about 0.001 to about 5% by weight of thetotal compositions, preferably from about 0.001 to about 1%.

Other active ingredients such as sunscreen materials and antimicrobialmaterials may be utilized in the compositions of the present inventionprovided that they are physically and chemically compatible with theother components of the compositions. For example, moisturizing agentssuch as propylene glycol, allantoin, acetamine MEA, oat protein andhyaluronic acid and other humectants may be added to theretinoid-containing formulations of this invention in order to providemoisturizing activity in conjunction with the retinoid-related activityof the products. Other proteins and amino acids may also beincorporated. Sunscreens may include organic or inorganic sunscreens,such as octylmethoxycinnamate and other cinnamate compounds, titaniumdioxide and zinc oxide and the like.

Various irritancy mitigants may be added to the compositions of thisinvention. Retinoid-containing compositions tend to irritate the skin,therefore irritancy mitigants assist in preventing undue discomfort tothe user, while potentially permitting the dosage level of retinoid tobe increased, thereby making the product more effective. Irritancymitigants such as α-bisabolol, panthenol, green tea extract, allantoin,ginkgo biloba, stearoyl glycyrrhetinic acid (licorice extract), tea treeoil, butchers' broom, calendula, ginseng and the like may be added.

It has also been found, surprisingly, that certain materials provide amitigation of irritation due to retinoids which have not previouslyevidenced such irritation. For example, retinoid-containing compositionswhich also contain octylmethoxycinnamate had very low irritation on theskin when compared with identical compositions which did not containoctylmethoxycinnamate. Preferably, the octyl methoxycinnamate should bepresent in an amount from about 3 to about 6. It is believed thatsimilar organic esters, such as homosalate, menthyl anthranilate,octocrylene, octyl dimethyl PABA, DEA methoxy cinnamate, octylsalicylate, TEA salicylate and ethyl dihydroxypropyl PABA are othercompounds which may also act as irritation mitigants with respect toretinoids. It is believed that such organic esters may control retinoiddelivery in that they may solubilize or associate with the retinoid.Alternatively, hydrolysis of these esters may produce aromaticcarboxylic acids, which may act as weak anti-inflammatory agents.

Other ingredients may include agents which assist in protecting the skinfrom aging, such as sunscreens, anti-oxidant vitamins such as ascorbicacid, vitamin B, biotin, pantothenic acid, vitamin D, vitamin E andvitamin C. Yeast extract, gingko biloba, bisabolol, panthenol, alphahydroxy acids and oligosaccharides such as melibiose are among otheringredients which assist in preventing aging of the skin by such meansas irritation mitigation, oxidation mitigation, healing, affectingretinoid metabolism and inhibiting the production of elastase.

Skin color evening ingredients and depigmentation agents may also beeffective in the products of this invention. Such ingredients mayinclude hydroquinone, licorice extract, kojic acid, gatuline A (pilewortextract), micromerol (butylene glycol and apple extract), glutathione,arbutin, placenta extract, ascorbic acid,magnesium-L-ascorbyl-2-phosphate and the like.

Compositions which assist in the reduction of lines and wrinkles mayalso be added to the compositions of this invention. For example, alphahydroxy acids, hyaluronic acid, Gatuline R (fagus silvitica extract),pigments and scattering aids such as mica, zinc oxide and titaniumdioxide may be used in the compositions of this invention in thiscapacity. Various natural extracts such as tannins, flavenoids, saponinsand the like may also be added.

Anti-inflammatory agents may also be used in the compositions of thisinvention. Not only should these agents assist in mitigating irritation,they may assist the retinoids in treating wrinkles and lines in theskin. Steroidal anti-inflammatory agents, including but not limited to,corticosteroids such as hydrocortisone, hydroxyltriamcinolone,alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasonedipropionate, clobetasol valerate, desonide, desoxycorticosteroneacetate, dexamethasone, dichlorisone, deflorasonediacetate,diflucortolone valerate, fluadronolone, fluclarolone acetonide,fludrocortisone, flumethasone pivalate, fluosinolone acetonide,fluocionide, flucortine butylester, fluocortolone, flupredidene(flupredylidene) acetate, flurandronolone, halcinonide, hydrocortisoneacetate, hydrocortisone butyrate, methylprednisolone, triamcinoloneacetonide, cortisone, cortodoxone, flucetonide, fludrocortisone,difluorosone diacetate, fluradrenalone acetonide, medrysone, amciafel,amcinafide, betamethasone and its esters, chlorprednisone acetate,clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide,flunisolide, fluoromethalone, fluperolone, fluprednisolone,hydrocortisone valerate, hydrocortisone cyclopentylpropionate,hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone,beclomethasone dipropionate, triamcinolone and mixtures thereof may beused. Preferably, hydrocortisone may be used.

Nonsteroidal anti-inflammatory agents may also be employed in thecompositions of this invention, such as salicylates (including alkyl andaryl esters of salicylic acid), acetic acid derivatives (includingarylacetic acid and its derivatives), fenamates, propionic acidderivatives and pyrazoles or mixtures thereof. Other synthetic andnatural anti-inflammatory agents may also be used.

Additional active ingredients having topical activity may be utilized inthe compositions of this invention. Azole-type anti-fungal andanti-bacterial agents may be employed in the compositions of thisinvention in their base form. For example, ketoconazole, miconazole,itraconazole, metronidazole, elubiol, and like related imidazoleantifungals and antibacterials are useful in the topical formulations ofthis invention.

The compositions of the present invention can be prepared by well-knownmixing or blending procedures. Each phase of the emulsion is preferablyseparately prepared with all of the components contained in theappropriate phase, except that it is usually preferred to omit theretinoid compound initially. The emulsion is then formed normally byadding the oil phase to the water phase with agitation. Preferably, thewater phase should be added into the oil phase, as it results inincreased stability. It is preferred that the portions be prepared underoxygen-depleted atmosphere such as a nitrogen or argon gas blanket. Mostpreferably, argon or nitrogen gas is bubbled through the water phaseprior to phasing in the oil phase. Commercially, it is envisioned thatsuch oxygen depleted atmosphere may be obtained by operating undervacuum conditions and that the product be stored, prior to use, inblind-end containers, preferably aluminum tubes.

This invention relates not only to stable and estheticretinoid-containing compositions used in skin care, and to methods ofmaking such compositions, it also relates to an apparatus and method ofstoring such compositions prior to use. Previously, numerous productscontaining retinol or its esters or aldehyde have been marketed inpackages which follow the convention for personal care products in beingcomposed of principally low or high density polyethylene orpolypropylene usually containing a pigmenting substance included withinthe package resin. Although this package technology is ordinarilysuitable for toiletries, it has been found that these package materialsare not satisfactory for retinoid materials, particularly retinol andretinal, as they transmit sufficient light combined with sufficientoxygen to lead to degradation of the vitamin substance into foreignmaterials not ordinarily found in mammalian metabolism, such as avariety of cis-isomers of the polyene moiety of the retinoid side chain,as well as oxidative degradation products and hydrolysis products. Ithas been found that a combination of proper manufacturing procedures asdescribed can provide the fresh product in suitable form to theconsumer, but over time, without exclusion of the destabilizinginfluences of light and oxygen, the foreign degradative substancesaccumulate, reducing the extent of the desirable attributes of theproduct.

In some cases, such as the retinaldehyde-containing product "Ystheal",commercially available from Pierre Fabre of France, a package structurewhich minimizes the tendency of the package to inhale air afterdispensing product has been used, thus minimizing the exposure ofproduct to oxygen. However, since the package is made of pigmentedpolypropylene, it is not sufficiently protective of light intrusion intothe product. Many package forms, such as plastic tubes, bottles, orjars, are ineffective in protecting product from either air or light.

The skin care composition should neither be directly contacted withoxygen or an oxygen-containing gas such as air, nor contacted withoxygen passing through the wall of the container. Portions in contactwith the outside, which constitute the container, such as a wall, anopening, etc. of the container, are required to have excellent oxygenbarrier properties. The container must also be designed not to passoxygen when feeding the skin care composition to the container or whenremoving the composition from the container.

If has been found that sufficient exclusion of these destructiveinfluences may be obtained only by use of packages constructed in partof aluminum, which is totally opaque to light and totally excludesoxygen permeation of the package walls. Additionally, given that thealuminum is not elastic, unlike plastic tubing, it has minimal tendencyto suck back air after dispensing product. Another package structurewhich is adequate to protect retinoid-containing products is thatconstructed with plastic film laminates including a layer of aluminumfoil. The aluminum foil provides the protection of the aluminum tube,while the plastic film layers permit more conventional packageesthetics. Another construction which is highly desirable for retinoidproduct protection is one which is constructed of aluminum foil oraluminum plastic laminate films of thin gauge and of broad and thindimensions, sufficient so that the package can collapse as product iswithdrawn, preventing air inhalation after product is dispensed. Suchfoil structures may be contained within a physically protective andesthetic oversleeve of conventional plastic, enabling safe shipping andhandling during processing, as well as when it reaches consumers.

It has also been found that by using a pouch-type container in which acomposition is out of contact with oxygen, the composition can be usedas not only a water-in-oil type emulsion but also an oil-in-water typeemulsion. Further, even after use is begun, the contact with oxygen canbe blocked, making it possible to substantially prevent decomposition ordegradation of the retinoid in the skin care composition.

More specifically, this invention relates to a container in which theskin care composition is out of contact with oxygen in a two-compartmentcontainer such as a pouch-type container, further to a skin carecomposition which is stored in a two-compartment container which aremade of films. Preferably, the film materials of the inner container areformed from a monolayer film or multilayer film. The film materials arepreferably selected from the following materials: aluminum and AAS andethylene-vinyl alcohol copolymer. More preferably, the pouch-typecontainer contains film materials which are laminated in the followingorder, beginning from the innermost portion of the film: polyethyleneterephthalate, nylon, aluminum and an AAS resin or polypropylene.Further, this invention relates to a skin care composition which isstored in a container having an aerosol-system using a liquefied gas ora compressed gas.

If such a requirement is satisfied, the shape of the container in whichthe composition is out of contact with oxygen is not particularlylimited in this invention, and can be a tube, a pump dispenser, acompressed dispenser, a bottle, a spray, a sachet or the like. From theaspects of production, treatment and an oxygen-barrier type, thetwo-compartment container is preferred and, the pouch-type container isespecially preferred. Such a two-compartment container generally means acontainer consisting of an outer container and an inner container whichis accommodated in the outer container and stores the content therein,but is not particularly restricted if the container can store andisolate the content from outside. A "pouch-type container" means acontainer having an outer container and a pouch which is accommodated inthe outer container, is provided with a valve which stores the contentstherein.

This pouch is a bag-like container whose wall is formed of a film andwhich is provided with an opening through which to pass the contents.The two-part container actually used is preferably an aerosol-system.The aerosol-system here referred to is a system in which the inside ofthe container is kept in a state pressurized with a propellant, and thecontent is sprayed with the propellant by opening a valve, or a systemin which the content is discharged outside the container with thepressure of the propellant.

A liquefied gas or a compressed gas is used as a propellant. Examples ofthe liquefied gas include chlorofluorocarbons, dimethyl ether, liquefiedpetroleum gas (LPG) and chlorinated hydrocarbons. Examples of thecompressed gas include a nitrogen gas, a carbon dioxide gas, a nitrousoxide (N₂ O) and argon. The liquefied gasses are preferable whenconsidering a uniformity of discharge amount of the content, and thecompressed gasses are preferable in minimizing interaction with thecontent, influence on the human body and the like.

An ordinary aerosol is generally formed by charging a stock solution andpropellant in a container and sealing the container with a valve. In ageneral filling method, the content is charged into the container froman opening, and after the opening is sealed with a valve the propellantis further charged. According to such an ordinary filling method,however, it is quite difficult to prevent the contact between thecontent such as a lotion or the like and oxygen. There is further aproblem that the content is directly contacted with the propellantwithin the pouch by being partially mixed therewith. Taking into accountthe problem of stability of the retinoid compound, the container of theordinary aerosol-system in which the content is mixed with thepropellant cannot be used in the skin care composition of thisinvention.

Accordingly, the two-part container in this invention, unlike theordinary container, consists of an outer container and a pouch having avalve. Only the content (skin care composition) is contained in theinner container and the propellant is not; along with the innercontainer, the propellant is stored in the outer container. Similarlythe pouch-type container of this invention consists of an outercontainer and a pouch having a valve. Only the skin care composition iscontained in the pouch and the propellant is not; along with the pouch,the propellant is stored in the outer container. Employment of such amethod prevents the contact between the skin care composition and thepropellant, thereby making it possible to prevent decomposition ordegradation of the retinoid in the skin care composition.

A method of filling the contents in the inner container is notparticularly limited and methods such that the oxygen does not invadethe inner container and not contact the contents may be applicable, asknown to those of ordinary skill in the art. Preferably, the contactbetween oxygen and the skin care composition of this invention should beperformed such that filling takes place in an atmosphere of inert gassuch as nitrogen or argon. The content is filled in the pouch asfollows. First, the pouch and propellant are placed within the outercontainer and said outer container is then sealed with the valve. Inthis state, a gas within the pouch is expelled with the pressure of thepropellant so that the inside of the pouch is almost completelydegassed. After that, the content is filled in the pouch under pressure.The content is, when filled by this method, scarcely contacted withoxygen in the filling. Preferably, if the content is filled in inert gassuch as nitrogen or argon, the contact with oxygen is more completelyblocked.

Further, even after the content is filled, it is double partitioned fromthe open air by an oxygen-impermeable film used in the pouch and theouter container, and the contact between oxygen in an ambient atmosphereand the skin care composition within the pouch is completely prevented.

The conventional tube-type container is completely sealed before firstopened. However, once it is opened and started to be used, entrance ofoxygen is permitted whenever it is opened for use, though the contactwith air is prevented with a cap during storage. Meanwhile, when thetwo-part container is used, oxygen does not enter even after starting touse it.

The material of the container of this invention in which the compositionis out of contact with oxygen is not particularly limited. However, amultilayered film constituting the inner container in thetwo-compartment container is preferable, from the aspects of sealingretention, oxygen-barrier properties and stability to the skin carecomposition. More preferable is a multilayered film composed of at leasttwo kinds selected from the group consisting of polyethyleneterephthalate, nylon, aluminum, polypropylene, an AAS resin and anethylene/vinyl alcohol copolymer. Especially preferable are amultilayered film obtained by laminating polyethylene terephthalate,nylon, aluminum and the AAS resin in this order as film materials fromthe innermost layer to the outermost layer of the pouch, and amultilayered film obtained by laminating polyethylene terephthalate,nylon, aluminum and polypropylene in this order as materials from theinnermost layer to the outermost layer.

Polyethylene terephthalate is a polyester resin having a chemicalstructure obtained by polycondensing terephthalic acid with ethyleneglycol. Nylon includes various polyamide resins. The AAS resin is aresinous polymer formed by graft polymerizing acrylonitrile as a maincomponent with copolymer components including an acrylate ester andbutadiene, and can be obtained, for example, under a trade name "BAREX"from Mitsui Toatsu Chemicals, Inc.

The ethylene/vinyl alcohol copolymer is a resinous polymer produced bysaponifying a random copolymer of ethylene and vinyl acetate, and beobtained, for example, under a trade name "EVAL" from Kuraray Co., Ltd.

The two-part container of this invention can be used, as is apparentfrom the foregoing explanation, in not only the retinoid-containing skincare composition but also liquid substances of various forms, e.g., anemulsion, a suspension, an aqueous solution and an oil. Especially, itis suitable for storage of substances required to protect the contentfrom an external environment such as air.

FIG. 1 is a front view of an example of an outer container in which thepouch of this invention is placed. When a cap is pushed down, a skincare composition is injected from an opening of a valve.

FIG. 2 is a front view of the pouch in this invention.

FIG. 3 is a sectional view of a multilayered film used in the pouch.

FIG. 4 is a graph representing retinol stability in differentanti-oxidants at 40 C.

The advantages of the invention and specific embodiments of the skincare compositions prepared in accordance with the present invention areillustrated by the following examples. It will be understood, however,that the invention is not confined to the specific limitations set forthin the individual examples, but rather to the scope of the appendedclaims.

EXAMPLE 1

The formulations of this Example 1 were prepared by first creating thewater phase and then creating the oil phase. After both phases werecreated, they were mixed together and retinol added. The water phase wasmade by first weighing deionized water into a beaker and, with mixing athigh speed, slowly adding carboxy polymer (carbomer). The mixture wasthen stirred for a few minutes. EDTA and ascorbic acid were added to themixture and mixing was continued for forty-five minutes or untilwell-dissolved. The water phase was then heated to 80° C., at which timepropylene glycol was added. To make the oil phase, all ingredients ofthe oil phase were weighed and added together in a separate beaker. Theoil phase was then heated to 80 C. with mixing until homogeneous. Theoil phase was then slowly phased into the water phase with mixing. Afterphasing, the emulsion was apportioned into four parts and sodiumhydroxide was added at 80° C. to each portion separately in order toadjust the pH of the emulsion. The portions were adjusted to have pH of4.5, 6.0, 7.0 and 9.0, respectively. After mixing for ten minutes, theemulsion was cooled to 45° C. Retinol 40% was then added to theemulsions and the emulsions mixed until homogeneous. The procedure wascarried out under yellow light and under an argon blanket so as tominimize exposure to oxygen. Retinol concentrations were measured inaccordance with the general HPLC procedure set forth below in Example 2,however, a different column was used containing a mobile phase of 65%acetonitrile, 35% phosphate buffer and a C18 column and a UV detector at325 nm.

The components of the formulations of this example were as follows:

    ______________________________________                                        Components        Content (% W/W)                                             ______________________________________                                        Carboxyvinyl polymer                                                                             0.300                                                        Propylene glycol 5.00                                                         Methylparaben 0.15                                                            Ascorbic Acid 0.10                                                            Glyceryl monostearate & 5.00                                                  PEG 100 Stearate                                                              Cetanol (cetyl alcohol) 1.00                                                  Stearyl alcohol 0.50                                                          White Petrolatum 1.50                                                         BHT 0.05                                                                      Propylparaben 0.10                                                            Butylparaben 0.05                                                             Cetyl palmitate 1.00                                                          C12-C15 Alkyl Benzoate 4.00                                                   Benzyl alcohol 0.30                                                           Ethyl alcohol 4.00                                                            Disodium EDTA 0.05                                                            Retinol 40%  0.366                                                            Sodium Hydroxide (10%) to adjust pH                                           Water q.s.                                                                  ______________________________________                                    

The four emulsions were again apportioned into two parts each, and oneof each part held at 50° C., the other part held at 40° C. The stabilityof all four emulsions was measured over a period of eight weeks. Thestability data is set forth below in Table 1.

                  TABLE 1                                                         ______________________________________                                                                     % Retinol From                                     Weeks Temperature pH Initial                                                ______________________________________                                        2        50° C. 4.5   80.19                                                6.0 93.67                                                                     7.0 97.07                                                                     9.0 96.01                                                                   4 40° C. 4.5 82.65                                                       6.0 95.72                                                                     7.0 97.64                                                                     9.0 95.77                                                                    50° C. 4.5 64.35                                                        6.0 94.43                                                                     7.0 95.92                                                                     9.0 94.74                                                                   8 40° C. 4.5 74.98                                                       6.0 94.48                                                                     7.0 96.24                                                                     9.0 94.76                                                                    50° C. 4.5 45.13                                                        6.0 90.99                                                                     7.0 94.33                                                                     9.0 89.68                                                                 ______________________________________                                    

Thus, it can be seen that, although acceptable stabilities can beachieved at pH about 4.5, higher pH yields increased stability in theformulations of this invention.

EXAMPLE 1A

An oil-in-water emulsion was prepared in accordance with the procedureset forth in Example 1, using the components set forth below. Again, theemulsion was divided into four parts and the pH adjusted, this time to4.5, 6.0, 8.0 and 10.0. Each part was further divided into two portions,one being held at 40° C. and one held at 50° C. for a period of sevenweeks.

The results of the stability measurement are set forth in Table 1Abelow. Again, it can be seen that, as the pH increased, the stabilityincreased.

    ______________________________________                                        Components       Content (% W/W)                                              ______________________________________                                        Disodium EDTA    0.10                                                           Ascorbic Acid 0.10                                                            Methylparaben 0.15                                                            Mineral Oil 8.00                                                              Stearyl Alcohol 1.00                                                          BRIJ 721 (Steareth 21) 2.00                                                   BRIJ 72 (Steareth-2) 2.00                                                     BHT 0.05                                                                      Propylparaben 0.10                                                            Retinol 40%  0.366                                                            Deionized Water Q.S.                                                          Sodium Hydroxide 10% to adjust pH                                           ______________________________________                                    

                  TABLE 1A                                                        ______________________________________                                                                     % Retinol From                                     Weeks Temperature pH Initial                                                ______________________________________                                        2       50° C. 4.5    87.87                                                6.0 95.63                                                                     8.0 98.37                                                                     10.0  96.95                                                                 7 40° C. 4.5 89.4                                                        6.0 94.0                                                                      8.0 95.4                                                                      10.0  96.3                                                                   50° C. 4.5 75.0                                                         6.0 89.2                                                                      8.0 91.5                                                                      10.0  94.5                                                                ______________________________________                                    

EXAMPLE 2

As a skin care composition containing a retinoid, an oil-in-water typelotion having the formulation shown in Table 2 was prepared inaccordance with the procedure set forth in Example 1. As the retinoid,retinol was used. Concentrations of retinol and other retinoids such asretinal (vitamin A aldehyde), retinyl acetate and retinyl palmitate canbe determined by any suitable analytical procedure.

                  TABLE 2                                                         ______________________________________                                        Components         Content (% by Weight)                                      ______________________________________                                        Carboxyvinyl polymer                                                                             0.1                                                          Propylene glycol 5.0                                                          Methylparaben 0.15                                                            Sodium hydroxide 0.04l                                                        Ascorbic acid 0.1                                                             Glyceryl monostearate & 5.0                                                   PEG 100 Stearate                                                              Cetanol 1.0                                                                   Stearyl alcohol 0.5                                                           White Petrolatum 1.5                                                          BHT 0.05                                                                      Propylparaben 0.1                                                             Butylparaben 0.05                                                             Cetyl palmitate 1.0                                                           Higher alcohol benzoic acid ester 4.0                                         Benzyl alcohol 0.3                                                            Ethyl alcohol 5.0                                                             Disodium edetate 0.05                                                         Retinol 0.075                                                                 Purified water q.s.                                                           Total 100                                                                   ______________________________________                                    

A storage test was performed using three pouch-type aerosol containersof this invention which consisted of a pouch and contained LPG as apropellant correspondingly to the three test temperatures shown in Table3. The pouch of said aerosol container was produced with a four-layeredfilm obtained by laminating polyethylene terephthalate, nylon, aluminumand an AAS resin in this order as film materials from the innermostlayer to the outermost layer. The above skin care composition wasdistributed in each of the three containers to form three samples. Themethod of distribution of the skin care composition is as follows.First, the pouch is placed in the outer container and LPG is charged inthe outer container and outside of the pouch and sealed, thereby a gasin the pouch is expelled with the pressure of the LPG. In this state,the skin care composition is filled in the pouch under pressure. Thethree samples were allowed to stand in a constant temperature chamberadjusted to 40° C.±1° C., a constant temperature chamber adjusted to 4°C.±1° C. and at room temperature. Samples for analysis were collectedfrom the same samples through an injection nozzle with the pressure ofthe propellant before the start of the test, 4 weeks later, 8 weekslater and 13 weeks later. One gram of each sample for analysis wasaccurately weighed and collected. A retinoid was extracted with an ethylacetate/methanol mixed solution, and an amount of the retinoid wasdetermined by a light absorption analysis at a wave length of 325 nmusing a liquid chromatograph. As reported herein, we determined retinoidconcentrations by a high performance liquid chromatography (HPLC)procedure in which the chromatograph was equipped with a reversed phase5 micron C-8 column (25 cm in length×4.6 mm in diameter) and a UVdetector at 340 nm. The sample to be analyzed was diluted with asolution of 50% by weight methanol and 50% by weight ethyl acetate to aconcentration of 18 micrograms/ml and the retinoid was detected at 340nm. The gradient mobile phase consisted of an organic portion composedof 5 percent tetrahydrofuran in acetonitrile and an aqueous portionconsisting of 0.05N ammonium acetate. The solvent program has an initialcomposition of 70% organic/30% aqueous which increases linearly to 80%organic /20% aqueous at 3 minutes, then again increases linearly to 100%organic at 15 minutes, where it stays until 19 minutes. After injecting15 microliters of sample solution into the chromatograph, the analyticalconditions were run at a flow rate of 2 ml/min and thermostaticallyregulated at 40° C. The retention time of retinol (Vitamin A alcohol) isabout 6.4 minutes. The retention times of retinal (vitamin A aldehyde),retinyl acetate, and retinyl palmitate are about 7.5 mins., 10.1 mins.and 18.7 mins., respectively. The HPLC results were found to bereproducible to better than a 3% range of standard deviation. Theresults are shown in Table 3 below.

EXAMPLE 3

The storage test was performed to determine the amount of a retinoid inthe same manner as in Example 2 except that a pouch was used which wasproduced with a four-layered film obtained by laminating polyethyleneterephthalate, nylon, aluminum and polypropylene in this order asmaterials form the innermost layer to the outermost layer, that anitrogen gas was used as a propellant and that the distribution of theskin care composition is performed by the following method, a pouch isplaced in an outer container then the skin care composition is filled inthe pouch, the pouch is sealed with a valve, a nitrogen gas is chargedinside the outer container and outside the pouch and sealed. The resultsare shown in Table 3.

Comparative Examples 1 and 2

The storage test was performed to determine the amount of a retinoid inthe same manner as in Example 1 at the temperature listed in Table 3below, except using a sealed aluminum tube in Comparative Example 1, anaerosol container not using a pouch in Comparative Example 2. Theresults are shown in Table 3. When an aluminum tube was used, ninesealed samples were prepared. Under the respective temperatureconditions, the unopened sealed samples were opened 4 weeks later, 8weeks later and 13 weeks later, and samples for analysis were thencollected.

                  TABLE 3                                                         ______________________________________                                        Example No.                                                                           Temperature                                                                             4 weeks later                                                                           8 weeks later                                                                         13 weeks later                            ______________________________________                                        Example 1                                                                             40° C.                                                                           90.7      88.9    93.2                                         room temp. 93.4 90.3 92.0                                                     4° C. 95.1 93.0 94.9                                                  Example 2 40° C. 89.0 87.0 86.2                                         room temp. 92.0 87.9 88.6                                                     4° C. 93.2 91.2 91.6                                                  Comparative 40° C. 83.5 80.9 80.7                                      Example 1 room temp. 86.6 88.0 82.1                                            4° C. 89.5 86.8 88.7                                                  Comparative 40° C. 85.0 85.3 81.4                                      Example 2 room temp. 89.3 86.5 86.9                                         ______________________________________                                    

EXAMPLE 4

An oil-in-water type lotion having a formulation shown in Table 4 wasprepared. The lotion was filled in the pouch-type aerosol container andthe storage test for four weeks and eight weeks was performed as inExample 2 except that a nitrogen gas was used as a propellant.

                  TABLE 4                                                         ______________________________________                                        Components        Content (% by weight)                                       ______________________________________                                        Carboxyvinyl polymer                                                                            0.25                                                          Propylene glycol 5.0                                                          Methylparaben 0.15                                                            Sodium hydroxide 0.041                                                        Ascorbic acid 0.1                                                             Glyceryl monostearate & PEG 5.0                                               100 Stearate                                                                  Cetanol 1.0                                                                   Stearyl alcohol 0.5                                                           White Petrolatum 1.5                                                          BHT 0.05                                                                      Propylparaben 0.1                                                             Butylparaben 0.05                                                             Cetyl palmitate 1.0                                                           Higher alkyl benzoic acid ester 4.0                                           Benzyl alcohol 0.3                                                            Ethyl alcohol 5.0                                                             Disodium edetate 0.05                                                         Retinol 0.075                                                                 Purified water q.s.                                                           Total 100                                                                   ______________________________________                                    

Comparative Example 3

The lotion prepared in Example 3 was filled in a jar container and thestorage test for four weeks and eight weeks was performed as in Example3. The results of Example 3 and Comparative Example 3 are shown in Table5.

                  TABLE 5                                                         ______________________________________                                        Example No.                                                                              Temperature                                                                              4 weeks later                                                                           8 weeks later                                 ______________________________________                                        Example 3  40° C.                                                                            95.7      94.9                                             room temp. 96.4 96.0                                                          4° C. 97.0 99.9                                                       Comparative 40° C. 70.0 62.8                                           Example 3 room temp. 94.6 90.3                                                 4° C. 96.1 98.9                                                     ______________________________________                                    

EXAMPLE 4

An oil-in-water type lotion having the formulation shown in Table 6 wasprepared.

                  TABLE 6                                                         ______________________________________                                        Components        Content (% by weight)                                       ______________________________________                                        Carboxyvinyl polymer                                                                            0.3                                                           Propylene glycol 5.0                                                          Methylparaben 0.15                                                            Sodium hydroxide 0.041                                                        Ascorbic acid 0.1                                                             Glyceryl monostearate & 5.0                                                   PEG 100 Stearate                                                              Cetanol 1.0                                                                   Stearyl alcohol 0.5                                                           White Petrolatum 1.5                                                          BHT 0.05                                                                      Propylparaben 0.1                                                             Butylparaben 0.05                                                             Cetyl palmitate 1.0                                                           Higher alkyl benzoic acid ester 4.0                                           Benzyl alcohol 0.3                                                            Ethyl alcohol 5.0                                                             Disodium edetate 0.05                                                         Retinol 0.075                                                                 Purified water q.s.                                                           Total 100                                                                   ______________________________________                                    

The storage test was performed in the same manner as in Example 1 exceptthat a two-compartment container whose propellant is LPG was used andthat the distribution of the skin care composition is performed in anatmosphere of an inert gas. The results are shown in Table 7.

Comparative Example 4

The lotion prepared in Example 4 was filled in a jar container and thestorage test was performed as in Example 4. The results of ComparativeExample 4 are shown in Table 7.

                  TABLE 7                                                         ______________________________________                                        Example No.                                                                           Temperature                                                                             4 weeks later                                                                           8 weeks later                                                                         13 weeks later                            ______________________________________                                        Example 4                                                                             40° C.                                                                           92.6      89.2    87.4                                         room temp. 93.4 90.7 91.0                                                     4° C. 98.1 95.2 93.5                                                  Comparative 40° C. 81.1 77.6 52.5                                      Example 4 room temp. 91.0 82.6 84.8                                            4° C. 92.4 91.7 92.7                                                ______________________________________                                    

EXAMPLE 5

A formulation was prepared in accordance with the procedure set forth inExample 1, except that the following components were used.

    ______________________________________                                                       Content (% by weight)                                          Components       Formula A                                                                              Formula B                                           ______________________________________                                        Deionized Water  Q.S      Q.S                                                   Sorbitol 5.0   5.00                                                           Methylparaben 0.15 0.15                                                       Disodium EDTA 0.02 0.02                                                       Span 60 3.00 3.00                                                             Tween 60 4.00 4.00                                                            Beeswax 0.95 0.95                                                             Safflower oil 3.33 0.00                                                       Liquid Paraffin 4.94 8.27                                                     BHT 0.03 0.03                                                                 Propylparaben 0.10 0.10                                                       Fragrance 0.15 0.15                                                           Retinol 40% 0.37 0.37                                                       ______________________________________                                    

The formulations A and B were divided into two. One portion each offormulation A and B was held at 40° C.; one portion each of formulationA and B was held at 50° C. for one week. After one week, stability ofthe retinol was measured. The results are set forth in Table 8 below. Itcan be seen that, after one week, formulation A, which containssafflower oil, an unsaturated oil, has significantly less retinol thanthat of formulation B, which does not contain unsaturated safflower oil.

                  TABLE 8                                                         ______________________________________                                                         % Retinol From Initial                                       Weeks    Temperature   Formula A                                                                              Formula B                                     ______________________________________                                        1        40° C. 89.0     92.0                                             50° C. 84.0 91.5                                                    ______________________________________                                    

EXAMPLE 6

The formulations of this example 6 were prepared by the procedure setforth in Example 1.

    ______________________________________                                        Component   6-I     6-II    6-III 6-IV  6-V                                   ______________________________________                                        Vitamin A Alcohol                                                                          0.166   0.166   0.166                                                                               0.166                                                                               0.166                                  Carbomer 0.30 0.30 0.30 0.30 0.30                                             Propylene Glycol 5.00 5.00 5.00 5.00 5.00                                     Methyl Paraben 0.15 0.15 0.15 0.15 0.15                                       Sodium Hydroxide 1.00 1.00 1.00 1.00 1.00                                     10% solution                                                                  Ascorbic Acid -- -- -- -- 0.10                                                Glyceryl Stearate 5.00 5.00 5.00 5.00 5.00                                    & PEG-100 Stearate                                                            Cetyl Alcohol 1.00 1.00 1.00 1.00 1.00                                        Stearyl Alcohol 0.50 0.50 0.50 0.50 0.50                                      White Petrolatum 1.50 1.50 1.50 1.50 1.50                                     Butylated Hydroxy-- -- -- 0.05 0.05 0.05                                      toluene                                                                       Propyl Paraben 0.10 0.10 0.10 0.10 0.10                                       Butyl Paraben 0.05 0.05 0.05 0.05 0.05                                        C12-15 Alkyl 4.00 4.00 4.00 4.00 4.00                                         Benzoate                                                                      Cetyl Palmitate 1.00 1.00 1.00 1.00 1.00                                      Benzyl Alcohol 0.30 0.30 0.30 0.30 0.30                                       SD Alcohol 40-B 5.00 5.00 5.00 5.00 5.00                                      Disodium EDTA -- 0.05 -- 0.05 0.05                                            Deionized Water q.s. q.s. q.s. q.s. q.s.                                    ______________________________________                                    

The stability of the formulations was measured by determining the amountof all-trans retinol after storage for various time periods at 40° C.

The results of this Example 6 are set forth in the graph in FIG. 4hereto. After 13 weeks of aging, all the Formulations I-V retained atleast 70% of the initial all-trans retinol in the compositions. Theaddition of a chelator, EDTA in Formulation 6-II improved the stabilityto a small extent. The addition of BHT, an oil-soluble anti-oxidant, inFormulation 6-III resulted in a relatively large improvement instability. The use of both EDTA and BHT in Formulation 6-IV alsoresulted in another improvement. The use of a chelator, an oil-solubleanti-oxidant and ascorbic acid, a water-soluble anti-oxidant, inFormulation 6-V, resulted in an excellent stability, retainingapproximately 90% of the initial all-trans retinol not only at 13 weeks,but at 25 weeks as well.

EXAMPLE 7

Another formulation in accordance with this invention contains thefollowing ingredients:

    ______________________________________                                        Ingredient        % W/W                                                       ______________________________________                                        Deionized Water   83.38                                                         Carbomer 0.35                                                                 Methylparaben 0.20                                                            Disodium EDTA 0.10                                                            D-Panthenol 0.50                                                              Glycerin 3.00                                                                 C12-15 Alkyl Benzoate 4.00                                                    Octyl Hydroxystearate 1.00                                                    Dimethicone 100 cs 1.00                                                       Cetyl Alcohol 2.50                                                            Cetearyl Alcohol 1.40                                                         & Cetearyl Glucoside                                                          BHT 0.10                                                                      Tocopherol Acetate 0.50                                                       Propylparaben 0.10                                                            Triethanolamine 99% 0.40                                                      Tocopherol 0.05                                                               Retinol 40%  0.118                                                            Japanese Tea Extract 1.00                                                     Diazolidinyl Urea 0.30                                                      ______________________________________                                    

The formulation of this Example 7 was found to be quite stable and is anacceptable emulsion for use on the face and other skin.

EXAMPLE 8

Another formulation in accordance with this invention contains thefollowing ingredients:

    ______________________________________                                                          Example 8-I                                                   Ingredient % W/W                                                            ______________________________________                                        Deionized Water   q.s.                                                          Carbomer 0.35                                                                 Methylparaben 0.20                                                            Disodium EDTA 0.10                                                            D-Panthenol 0.50                                                              Glycerin 3.00                                                                 C12-15 Alkyl Benzoate 4.00                                                    Octyl Hydroxystearate 1.00                                                    Dimethicone 100 cs 1.00                                                       Cetyl Alcohol 2.50                                                            Ceteryl Alcohol & 1.40                                                        Cetearyl Glucoside                                                            BHT 0.10                                                                      Tocopherol Acetate 0.50                                                       Propylparaben 0.10                                                            Deionized Water 1.50                                                          Triethanolamine 99% 0.40                                                      Tocopherol 0.05                                                               Retinol 40%  0.3825                                                           Japanese Tea Extract 1.00                                                     Deionized Water 2.00                                                          Diazolidinyl Urea 0.30                                                      ______________________________________                                    

The formulation of this Example 8-I is quite stable and is an acceptableemulsion for use on the face and other skin. After thirteen weeks ofstorage at 40C., 97% of the initial level of all-trans retinol waspresent in the composition of this example.

Another formulation was prepared in accordance with the procedure ofthis example, having the following formulation:

    ______________________________________                                                          Example 8-II                                                  Ingredient % W/W                                                            ______________________________________                                        Deionized Water   q.s.                                                          Carbomer 0.35                                                                 Methylparaben 0.20                                                            Disodium EDTA 0.10                                                            D-Panthenol 0.50                                                              Glycerin 3.00                                                                 C12-15 Alkyl Benzoate 4.00                                                    Octyl Hydroxystearate 2.00                                                    Cetyl Alcohol 2.50                                                            Cetearyl Glucoside 2.50                                                       BHT 0.10                                                                      Tocopherol Acetate 0.50                                                       Propylparaben 0.10                                                            Deionized Water 1.50                                                          Triethanolamine 99% 0.40                                                      Tocopherol 0.05                                                               Retinol 40%  0.3825                                                           Japanese Tea Extract 1.00                                                     Deionized Water 2.00                                                          Diazolidinyl Urea 0.30                                                      ______________________________________                                    

The formulation of this Example 8-II is quite stable and is anacceptable emulsion for use on the face and other skin. After thirteenweeks of storage at 40° C., 88% of the initial level of all-transretinol was present in the composition of this example.

EXAMPLE 9A

A sunscreen-containing formulation may be made in accordance with theprocedure set forth in Example 1, containing retinol and an activeinorganic sunscreen ingredient, titanium dioxide. The formulation ofthis example is as follows:

    ______________________________________                                        Ingredient             % W/W                                                  ______________________________________                                        Deionized Water        q.s.                                                     Carbomer 0.350                                                                Glycerine 3.00                                                                Panthenol 0.50                                                                Disodium EDTA 0.10                                                            C12-15 Alkyl Benzoate 4.00                                                    Octyl hydroxystearate 12.00                                                   Titanium Dioxide 4.00                                                         Dimethicone 1.00                                                              Cetearyl alcohol and cetearyl glucoside 1.40                                  Retinol 10% 0.46                                                              Cetyl Alcohol 2.50                                                            Tocopheryl Acetate 0.50                                                       Butylated Hydroxytoluene 0.10                                                 Triethanolamine 0.40                                                          Polysorbate 20 0.102                                                          Propyl paraben 0.10                                                           Tocopherol 0.05                                                               Paraben blend 0.40                                                          ______________________________________                                    

EXAMPLE 9B

Another formulation was created containing an organic sunscreen andretinol. The organic sunscreen used was octyl methoxycinnamate. Thisformulation had sunblock activity as well as having the other attributesof retinoid-containing formulations. The formulation was as follows:

    ______________________________________                                        Ingredient           % W/W                                                    ______________________________________                                        Deionized Water      66.84                                                      Glycerine 5.00                                                                Panthenol 0.50                                                                Disodium EDTA 0.20                                                            Allantoin 0.15                                                                Carbomer 0.30                                                                 Sodium metabisulfite 0.10                                                     Octyl Methoxycinnamate 6.00                                                   Glyceryl Stearate 5.00                                                        & PEG-100 Stearate                                                            C12-C15 Alkyl Benzoate 4.00                                                   White Petrolatum 1.50                                                         Lauroyl Lysine 1.00                                                           Cetyl Alcohol 1.00                                                            Cetyl Palmitate 1.00                                                          Steaeyl Alcohol 0.50                                                          Retinol 10% 0.46                                                              Butylated Hydroxytoluene 0.05                                                 SD Alcohol 40-B 5.00                                                          Sodium Hydroxide 1.00                                                         Isopropylparaben, 0.40                                                        Isobutylparaben, N-Butylparaben                                             ______________________________________                                    

EXAMPLE 10

In yet another formulation, a retinol-containing composition was madefor topical use. The composition was made in accordance with Example 1above. The ingredients were as follows:

    ______________________________________                                        Ingredient           % W/W                                                    ______________________________________                                        Deionized Water      72.84                                                      Glycerine 5.00                                                                Panthenol 0.50                                                                Disodium EDTA 0.20                                                            Allantoin 0.15                                                                Carbomer 0.30                                                                 Sodium metabisulfite 0.10                                                     Glyceryl Stearate 5.00                                                        & PEG-100 Stearate                                                            C12-C15 Alkyl Benzoate 4.00                                                   White Petrolatum 1.50                                                         Lauroyl Lysine 1.00                                                           Cetyl Alcohol 1.00                                                            Cetyl Palmitate 1.00                                                          Stearyl Alcohol 0.50                                                          Retinol 10% 0.46                                                              Butylated Hydroxytoluene 0.05                                                 SD Alcohol 40-B 5.00                                                          Sodium Hydroxide 1.00                                                         Isopropylparaben, 0.40                                                        Isobutylparaben, N-Butylparaben                                             ______________________________________                                    

EXAMPLE 11

Formulations in accordance with this invention may also be madecontaining azole-type compounds, such as itraconazole, miconazole andketoconazole. The nitrate or other salt forms of the imidazoles shouldnot be used, however, as they tend to render unstable the retinoidscontained in the formulations. In this example, the followingingredients were combined to make imidazole-containing formulationsaccording to the teachings of this invention.

    ______________________________________                                                        % W/W                                                         Ingredient      11-I      11-II    11-III                                     ______________________________________                                        Water Phase                                                                     Deionized Water q.s. 100% q.s. 100% q.s. 100%                                 Carbomer 940 0.22 0.22 0.22                                                   Disodium EDTA dihydrate 0.10 0.10 0.10                                        Propylene Glycol 5.00 5.00 5.00                                               Oil Phase                                                                     Arlacel 165 5.0 5.0 5.0                                                       Cetyl Alcohol 1.0 1.0 1.0                                                     Stearyl Alcohol 0.5 0.5 0.5                                                   White Petrolatum 1.5 1.5 1.5                                                  BHT 0.05 0.05 0.05                                                            Methylparaben 0.15 0.15 0.15                                                  Propylparaben 0.1 0.1 0.1                                                     Butylparaben 0.05 0.05 0.05                                                   C12-15 Alkyl benzoate 4.0 4.0 4.0                                             Cetyl Palmitate 1.0 1.0 1.0                                                   Ketoconazole 2.0 --  --                                                       Miconazole base --  2.0 --                                                    Miconazole nitrate -- --  2.0                                                 Ethyl Alcohol 5.0 5.0 5.0                                                     Benzyl Alcohol 0.3 0.3 0.3                                                    Refinol 40% 0.332 0.332 0.332                                                 Sodium Hydroxide (adjust pH)                                                ______________________________________                                    

The formulations were made in accordance with the procedures set forthin Example 1, except that the imidazoles were added to the oil phaseimmediately before phasing the oil phase into the water phase. Thestability of formulation 11-I at thirteen weeks of storage at 40° C. wassuch that 82% of the initial retinol was present. In formulation 11-II,after four weeks, 90% of the initial retinol remained compared with 71%of the initial retinol in formulation 11-III after four weeks. Thus,good stability was achieved in imidazole-containing formulationsaccording to this invention.

EXAMPLE 12

In another formulation, the following composition was prepared as anoil-in-water emulsion:

    ______________________________________                                        Ingredient         % W/W                                                      ______________________________________                                        Water Phase                                                                     Deionized Water 65.74                                                         Carbopol 934 (carboxy- 0.30                                                   vinyl polymer)                                                                Sodium EDTA 0.05                                                              Sodium bisulfite 0.10                                                         Butyl Paraben 0.05                                                            Methyl Paraben 0.15                                                           Propyl Paraben 0.01                                                           Allantoin 0.15                                                                Panthenol 0.50                                                                Propylene Glycol 5.00                                                         Oil Phase                                                                     Arlacel 165 5.00                                                              Cetyl Alcohol 1.00                                                            Stearyl Alcohol 1.50                                                          White Petrolatum 1.50                                                         Octyl Methoxycinnamate 6.00                                                   BHT 0.05                                                                      C12-15 Alkyl Benzoates 4.00                                                   Cetyl Palmitate 1.00                                                          Retinol Phase                                                                 Sodium Hydroxide @ 10% 1.00                                                   (solution w/w)                                                                Ethyl Alcohol 5.00                                                            Benzyl Alcohol 0.30                                                           Lauroyl lysine 1.00                                                           Retinol 10% 1.59                                                            ______________________________________                                    

Deionized water was weighed into a suitable beaker. Nitrogen gas wasbubbled through water, heat was applied and the water was mixed. At highspeed mixing, Carbomer was slowly added to deionized water, and mixedfor five minutes. The Disodium EDTA and sodium bisulfite were added tothis mixture. At 60° C, methyl, propyl, and butyl paraben were added, inaddition to allantoin and panthenol and the mixing continued. At 80° C.,propylene glycol was added and the composition mixed.

In a separate beaker, the oil phase ingredients were weighed one by onewhile heat was applied. The mixture was heated to 80° C. and mixed untilhomogeneous. The oil mixture was phased into the water phase slowly withmixing, and cooling was begun. At 60° C., the sodium hydroxide, lauroyllysine and Retinol were added individually. At about 35° C., ethylalcohol and benzyl alcohol were added and mixing continued for about 10minutes. Water was added q.s. and the formulation mixed for about fiveminutes until the batch was homogeneous.

The pH of the formulation of this example was about 6.6. The batchappeared creamy, glossy, smooth, homogeneous and off-white.

EXAMPLE 13

Retinaldehyde-containing compositions were made in accordance with thefollowing procedure. Operating under yellow light and an argon gasblanket, deionized water was weighed out in a beaker. Carbomer wasslowly added and the composition mixed well until dispersed. DisodiumEDTA and methyl paraben were added to the mixture and the mixture washeated to 80° C. At 80° C., propylene glycol was added. The oil phaseingredients were weighed and placed into a separate beaker. The mixturewas heated to 80° C. with stirring and dimethicone added. With bothphases at 80° C., the oil phase was added to the water phase and mixed.In formulation 13-I, a 50% sodium hydroxide solution was added for pHadjustment. Prior to adding the retinaldehyde, the mixture was held at80° C. for ten minutes, then cooled to 30° C. Retinaldehyde was mixedwith benzyl alcohol and added to the mixture. In formulation 13-II,citral was added to the premixture containing benzyl alcohol andretinaldehyde.

    ______________________________________                                                           % W/W                                                      Ingredient         13-I    13-II                                              ______________________________________                                        Water Phase                                                                     Deionized Water 82.29 82.29                                                   Carbomer 941 (carboxy- 0.30 0.30                                              vinyl polymer)                                                                Propylene Glycol 4.00 4.00                                                    Methylparaben 0.30 0.30                                                       Disodium EDTA 0.10 0.10                                                       Oil Phase                                                                     Myristyl Myristate 1.50 1.50                                                  Glyceryl Stearate 1.25 1.25                                                   stearic Acid 1.25 1.25                                                        Oleic Acid 1.25 1.25                                                          Polysorbate 61 1.20 1.20                                                      Isopropyl Palmitate 1.00 1.00                                                 Stearoxytrimethylsilane 1.00 1.00                                             Dimethicone 1.00 1.00                                                         Sorbitan Stearate 0.80 0.80                                                   Synthetic Beeswax 0.50 0.50                                                   Cetyl Alcohol 0.50 0.50                                                       Stearyl Alcohol 0.50 0.50                                                     BHT 0.02 0.02                                                                 Propylparaben 0.10 0.10                                                       Butylparaben 0.05 0.05                                                        Benzyl Alcohol 0.30 0.30                                                      Sodium Hydroxide 0.2 0.2                                                      Citral --  1.6                                                                Retinaldehyde 0.05 0.05                                                     ______________________________________                                    

Two other formulations containing retinaldehyde were made as follows.Deionized water was weighed into a beaker and with mixing at high speed,carbomer was added slowly. After a few minutes, EDTA was added, as wellas ascorbic acid. Mixing was continued for about 45 minutes until themixture was uniform. The mixture was heated to 80° C. and propyleneglycol added. In a separate beaker all oil phase ingredients wereplaced. The beaker was heated to 80° C. with mixing until homogeneous.The oils were then slowly phased into the water phase with mixing.Sodium hydroxide was added at 80° C. and the emulsion mixed for aboutten minutes. Cooling was begun. At 35° C., benzyl alcohol was added. Thebatch was q.s. to 997 gm weight with water. The emulsion was mixed untiluniform, about five minutes. The batch was then split into two portions.To one batch was added ethanol and retinaldehyde which had been premixedand dissolved. To the second batch was added a premix of ethanol, citraland retinaldehyde. The batches were then filled into blind aluminumtubes and stored at 40° C. for thirteen weeks. The formulations were asfollows:

    ______________________________________                                                          % W/W                                                       Ingredient        13-III  13-IV                                               ______________________________________                                        Water Phase                                                                     Deionized Water 75.85 74.25                                                   Carbomer 934P 0.30 0.30                                                       Disodium EDTA 0.05 0.05                                                       Ascorbic Acid 0.10 0.10                                                       Propylene Glycol 5.00 5.00                                                    Oil Phase                                                                     Glyceryl Monostearate &                                                       PEG 100 Stearate 5.0 5.0                                                      Cetyl Alcohol 1.0 1.0                                                         Stearyl Alcohol 0.5 0.5                                                       White Petrolatum 1.5 1.5                                                      BHT 0.05 0.05                                                                 Methylparaben 0.15 0.15                                                       Propylparaben 0.01 0.1                                                        Butylparaben 0.05 0.05                                                        C12-15 Alkyl benzoate 4.0 4.0                                                 Cetyl Palmitate 1.0 1.0                                                       Sodium Hydroxide 1.0 1.0                                                      10% (w/w soln.)                                                               Ethyl Alcohol 4.0 4.0                                                         Benzyl Alcohol 0.3 0.3                                                        Retinaldehyde 0.05 0.05                                                       Citral -- 1.6                                                               ______________________________________                                    

All four formulations of this example were stored for thirteen weeks at40° C. and had the following stabilities:

    ______________________________________                                        Stability    13-I   13-II      13-III                                                                             13-IV                                     ______________________________________                                        Conditions   65%    53%        65%  69%                                         13 wk/40° C.                                                         ______________________________________                                    

It is believed that, although the instability of retinal is even greaterthan that of retinol, through use of the methods and formulations ofthis invention, the stability can be improved. For example, an increasein pH in these formulations will result in an improved stability. Inexamples 13-I and 13-II, the C-value should be reduced as well.

EXAMPLE 14

Skin care compositions containing retinol with and withoutoctylmethoxycinnamate were prepared in an oil-in-water emulsion havingthe formulations set forth below. The method of preparation was similarto those of preceding examples.

    ______________________________________                                                            14A     14B                                               ______________________________________                                        Distilled Water     64.45   70.45                                               Carbomer 0.3 0.3                                                              Glycerin 5.0 5.0                                                              Panthenol, DL 0.5 0.5                                                         Allantoin 0.15 0.15                                                           Sodium metabisulfite 0.1 0.1                                                  Disodium EDTA 0.2 0.2                                                         Octylmethoxycinnamate 6.0 0.0                                                 Glyceryl Stearate & 5.0 5.0                                                   PEG 100 Stearate                                                              C12-C15 Alkyl Benzoate 4.0 4.0                                                White Petrolatum 1.5 1.5                                                      Lauroyl Lysine 1.0 1.0                                                        Cetyl Alcohol 1.0 1.0                                                         Cetyl Palmitate 1.0 1.0                                                       Stearyl Alcohol 0.5 0.5                                                       Butylated Hydroxytoluene 0.05 0.05                                            SD Alcohol 40B 5.0 5.0                                                        Retinol 0.165 0.165                                                           Soybean Oil 1.485 1.485                                                       Sodium hydroxide solution 1.0 1.0                                             Paraben mixture and 1.5 1.5                                                   phenoxyethanol                                                                Methyldihydrojasmonate 0.1 0.1                                              ______________________________________                                    

Examples 14A and 14B were submitted for human clinical studies toevaluate the irritation potential of the formulations. Products wererepeatedly placed on subjects' backs (n=200) under occlusion for aperiod of three successive weeks. Between applications of fresh product,the intensity of the irritation caused by the products was scored on a0-4 grading scale (0 representing no irritation and 4 representingintense erythema with edema and vesiculation). The irritation score forthe retinol containing product without octylmethoxycinnamate (14B) was267. For the product containing octylmethoxycinnamate (14A), theirritation score was 95, approximately one-third that of the productwithout the octylmethoxycinnamate. A second pair of formulae, with andwithout octylmethoxycinnamate were compounded to repeat this test and toconfirm this observation, as follows:

    ______________________________________                                                            14C     14D                                               ______________________________________                                        Distilled Water     68.075  74.075                                              Carbomer 0.3 0.3                                                              Glycerin 5.0 5.0                                                              Panthenol, DL 0.5 0.5                                                         Allantoin 0.15 0.15                                                           Disodium EDTA 0.2 0.2                                                         Water & Thea 1.0 1.0                                                          Sinensis (green tea) Extract                                                  Octylmethoxycinnamate 6.0 0.0                                                 Glyceryl Stearate & 5.0 5.0                                                   PEG 100 Stearate                                                              C12-C15 Alkyl Benzoate 4.0 4.0                                                White Petrolatum 1.5 1.5                                                      Lauroyl Lysine 0.5 0.5                                                        Cetyl Alcohol 1.0 1.0                                                         Cetyl Palmitate 1.0 1.0                                                       Stearyl Alcohol 0.5 0.5                                                       Butylated Hydroxytoluene 0.05 0.05                                            SD Alcohol 40B 2.5 2.5                                                        Retinol 0.165 0.165                                                           Soybean Oil 1.485 1.485                                                       Sodium hydroxide solution 0.675 0.675                                         (20%)                                                                         Isopropyl, isobutyl, 0.4 0.4                                                  & butylparabens                                                             ______________________________________                                    

A similar test was conducted with n=52 subjects. The irritation scorefor the product without the octyl-methoxycinnamate (14D) was 105.5, andfor the product with the octylmethoxycinnamate(14C) the irritation scorewas only 40.5, again, approximately one-third that of the formulawithout the octylmethoxycinnamate.

These results are particularly unexpected as octylmethoxycinnamate isconsidered to be a potentially irritating material. Previous irritationtests demonstrate that addition of octylmethoxycinnamate at 6% to aformula which did not contain a retinoid increases the level ofirritation. Two products were prepared as follows:

    ______________________________________                                                            14E     14F                                               ______________________________________                                        Distilled Water     65.66   71.88                                               Carbomer 0.3 0.3                                                              Glycerin 5.0 5.0                                                              Panthenol, DL 0.5 0.5                                                         Allantoin 0.15 0.15                                                           Sodium metabisulfite 0.1 0.1                                                  DiSodium EDTA 0.2 0.2                                                         Octylmethoxycinnamate 6.0 0.0                                                 Glyceryl Stearate & 5.0 5.0                                                   PEG 100 Stearate                                                              C12-C15 Alkyl Benzoate 4.0 4.0                                                White Petrolatum 1.5 1.5                                                      Lauroyl Lysine 1.0 1.0                                                        Cetyl Alcohol 1.0 1.0                                                         Cetyl Palmitate 1.0 1.0                                                       Stearyl Alcohol 0.5 0.5                                                       Butylated Hydroxytoluene 0.05 0.05                                            SD Alcohol 40B 5.0 5.0                                                        Soybean Oil 0.44 0.22                                                         Sodium hydroxide solution 1.0 1.0                                             Paraben mixture and 1.5 1.5                                                   phenoxyethanol                                                                Methyldihydrojasmonate 0.1 0.1                                              ______________________________________                                    

These formulae were also tested as indicated above in patch tests onhuman subject backs (n=200). The irritation scores for the productwithout the octylmethoxycinnamate (14F) was 21.5, while the irritationscore for the product with 6% octylmethoxycinnamate (14E) was 52, morethan twice as irritating. Unexpectedly, however, it appears that informulae containing retinol, the addition of octylmethoxycinnamatemitigates the irritation of the product.

EXAMPLE 16

A formulation in accordance with this invention was made using thefollowing ingredients, which compose a base vehicle for use in thecompositions of this invention:

    ______________________________________                                        Component CTFA Name                                                                              % (w/w)                                                    ______________________________________                                        Deionized Water    78.285                                                       Glycerin 5.000                                                                Carbomer 0.300                                                                Disodium EDTA 0.200                                                           Sodium Hydroxide 0.135                                                        Alcohol 2.780                                                                 Methylparaben 0.230                                                           Propylparaben 0.070                                                           Glyceryl Stearate & 5.000                                                     PEG 100 Stearate                                                              C12-15 Alkyl Benzoate 4.000                                                   White Petrolatum 1.500                                                        Cetyl Palmitate 1.000                                                         Cetyl Alcohol 1.000                                                           Stearyl Alcohol 0.500                                                         Total 100.00                                                                ______________________________________                                    

The water phase was prepared by measuring formula weight of water into asuitable vessel. The carbomer was slowly introduced to allow forhydration.

The vessel was then heated to about 70° C. At 70° C., glycerin and EDTAwere added. The composition was held at this temperature and mixed untilthe ingredients were dissolved. The water phase was then neutralizedwith TEA. The oil phase was then prepared separately by measuring alloil soluble ingredients into a suitable vessel, as follows: C12-15 alkylbenzoate, glyceryl stearate and PEG 100 stearate, white petrolatum,cetyl palmitate, cetyl alcohol and stearyl alcohol. The oil phase wasthen heated to 70° C. and the propylparaben and methyl paraben wereadded. The water phase was then slowly introduced to the oil phase,forming the emulsion. The emulsion was permitted to cool. When thetemperature of the emulsion reached 35° C., the alcohol was added andthe emulsion mixed until uniform. The batch was weighed and water addedto compensate for evaporation upon heating. pH was measured andadjusted.

Alternatively, the process for making the foregoing formulation may becarried out by adding the oil phase to the water phase. However,generally, better physical stability is achieved when the water phase isadded to the oil phase.

EXAMPLE 17

A formulation in accordance with this invention was made using thefollowing ingredients:

    ______________________________________                                        Component CTFA Name                                                                              % (w/w)                                                    ______________________________________                                        Deionized Water    85.95                                                        Carbomer 0.350                                                                Methylparaben 0.200                                                           Disodium EDTA 0.100                                                           Glycerin 3.000                                                                C12-15 Alkyl Benzoate 4.000                                                   Octyl Hydroxystearate 1.000                                                   Dimethicone 1.000                                                             Cetyl Alcohol 2.500                                                           Cetearyl Alcohol and 1.400                                                    Cetearyl Glucoside                                                            Propylparaben 0.100                                                           Triethanolamine 0.400                                                         Total 100.00                                                                ______________________________________                                    

The water phase was prepared by measuring formula weight of water intosuitable vessel. Carbomer was introduced slowly to allow for hydration.The phase was heated to 75° C. At temperature, glycerin and EDTA wereadded. The temperature was held and the phase mixed until theingredients were dissolved. The oil phase was prepared by measuringformula weight of the oil soluble ingredients into a suitable vessel, asfollows: C12-15 Alkyl Benzoate, Octyl hydroxystearate, Dimethicone,Cetyl Alcohol, Cetearyl Alcohol and Cetearyl Glucoside.

The oil phase was heated to 75° C. and the propylparaben and themethylparaben added. With the temperature of both phases at 75° C., theoil phase was slowly introduced to the water phase. The system wasneutralized with TEA. The batch was homogenized for a minimum of 1minute. The steps of introducing the phases coupled with homogenization,resulted in emulsion formation. The batch was weighed and water added tocompensate for evaporation upon heating. pH was measured and adjusted.

Alternatively, the process for making the foregoing formulation may becarried out by adding the oil phase to the water phase.

EXAMPLE 18

An emulsion was prepared in accordance with this invention which did notcontain a lower alkyl alcohol or detackifying material. The emulsion wasprepared in accordance with the procedure set forth in Example 15 andcontained the following ingredients:

    ______________________________________                                        Component CTFA Name                                                                              % (w/w)                                                    ______________________________________                                        Deionized Water    73.055                                                       Glycerin 5.000                                                                Panthenol 0.500                                                               Allantoin 0.150                                                               Carbomer 0.300                                                                Disodium EDTA 0.200                                                           Sodium Hydroxide 0.135                                                        Phenoxyethanol 0.700                                                          Methylparaben 0.230                                                           Propylparaben 0.070                                                           Glyceryl Stearate & 5.000                                                     PEG 100 Stearate                                                              Octylmethoxy- 6.000                                                           cinnamate                                                                     C12-15 Alkyl 4.000                                                            Benzoate                                                                      White Petrolatum 1.500                                                        Cetyl Palmitate 1.000                                                         Cetyl Alcohol 1.000                                                           Stearyl Alcohol 0.500                                                         Soybean Oil 0.460                                                             BHT 0.100                                                                     Vitamin E Acetate 0.100                                                     ______________________________________                                    

This formulation was functional as an emulsion, but exhibited some dragon application and tacky on drydown during application to the skin andwas somewhat grainy in texture.

EXAMPLE 19

An emulsion in accordance with the compositions of this invention wasprepared containing a detackifying material, lauroyl lysine, but withouta lower alkyl alcohol, having the following ingredients:

    ______________________________________                                        Component CTFA Name                                                                              % (w/w)                                                    ______________________________________                                        Deionized Water    72.555                                                       Glycerin 5.000                                                                Panthenol 0.500                                                               Allantoin 0.150                                                               Carbomer 0.300                                                                Disodium EDTA 0.200                                                           Sodium Hydroxide 0.135                                                        Phenoxyethanol 0.700                                                          Methylparaben 0.230                                                           Propylparaben 0.070                                                           Glyceryl Stearate & 5.000                                                     PEG 100 Stearate                                                              Octylmethoxy 6.000                                                            cinnamate                                                                     C12-15 Alkyl 4.000                                                            Benzoate                                                                      White Petrolatum 1.500                                                        Cetyl Palmitate 1.000                                                         Cetyl Alcohol 1.000                                                           Stearyl Alcohol 0.500                                                         Soybean Oil 0.460                                                             BHT 0.100                                                                     Vitarnin E Acetate 0.100                                                      Lauroyl Lysine 0.500                                                        ______________________________________                                    

This formulation held together well and was visually estheticallypleasing, without graininess. Upon application to the skin, it wassomewhat slow in spreading, but was non-tacky during drying.

EXAMPLE 20

An emulsion in accordance with the compositions of this invention wasprepared containing a lower alkyl alcohol, but without a detackifyingmaterial, lauroyl lysine, having the following ingredients:

    ______________________________________                                        Component CTFA Name                                                                             % (w/w)                                                     ______________________________________                                        Deionized Water   70.275                                                        Glycerin 5.000                                                                Panthenol 0.500                                                               Allantoin 0.150                                                               Carbomer 0.300                                                                Disodium EDTA 0.200                                                           Sodium Hydroxide 0.135                                                        Alcohol 2.780                                                                 Phenoxyethanol 0.700                                                          Methylparaben 0.230                                                           Propylparaben 0.070                                                           Glyceryl Stearate & 5.000                                                     PEG 100 Stearate                                                              Octylmethoxy- 6.000                                                           cinnamate                                                                     C12-15 Alkyl 4.000                                                            Benzoate                                                                      White Petrolatum 1.500                                                        Cetyl Palmitate 1.000                                                         Cetyl Alcohol 1.000                                                           Stearyl Alcohol 0.500                                                         Soybean Oil 0.460                                                             BHT 0.100                                                                     Vitamin E Acetate 0.100                                                     ______________________________________                                    

This formulation was smooth in applicatioin but tacky and draggy whiledrying upon the skin, but had satisfactory appearance and esthetics.

EXAMPLE 21

An emulsion in accordance with the compositions of this invention wasprepared containing both a lower alkyl alcohol, and a detackifyingmaterial, lauroyl lysine, having the following ingredients:

    ______________________________________                                        Component CTFA Name                                                                             % (w/w)                                                     ______________________________________                                        Deionized Water   69.775                                                        Glycerin 5.000                                                                Panthenol 0.500                                                               Allantoin 0.150                                                               Carbomer 0.300                                                                Disodium EDTA 0.200                                                           Sodium Hydroxide 0.135                                                        Alcohol 2.780                                                                 Phenoxyethanol 0.700                                                          Methylparaben 0.230                                                           Propylparaben 0.070                                                           Glyceryl Stearate & 5.000                                                     PEG 100 Stearate                                                              Octylmethoxy- 6.000                                                           cinnamate                                                                     C12-15 Alkyl 4.000                                                            Benzoate                                                                      White Petrolatum 1.500                                                        Cetyl Palmitate 1.000                                                         Cetyl Alcohol 1.000                                                           Stearyl Alcohol 0.500                                                         Soybean Oil 0.460                                                             BHT 0.100                                                                     Vitamin E Acetate 0.100                                                       Lauroyl Lysine 0.500                                                        ______________________________________                                    

This formulation had an excellent appearance, i.e., smooth and white,and was easy to spread and was not tacky upon drying on the skin.

EXAMPLE 22

A formulation was prepared having about 15 weight percent of ethylalcohol, as follows:

    ______________________________________                                        Component CTFA Name                                                                             % (w/w)                                                     ______________________________________                                        Deionized Water   57.555                                                        Glycerin 5.000                                                                Panthenol 0.500                                                               Allantoin 0.150                                                               Carbomer 0.300                                                                Disodium EDTA 0.200                                                           Sodium Hydroxide 0.135                                                        Alcohol 15.00                                                                 Phenoxyethanol 0.700                                                          Metbylparaben 0.230                                                           Propylparaben 0.070                                                           Glyceryl Stearate & 5.000                                                     PEG 100 Stearate                                                              Octylmethoxy- 6.000                                                           cinnamate                                                                     C12-15 Alkyl 4.000                                                            Benzoate                                                                      White Petrolatum 1.500                                                        Cetyl Palmitate 1.000                                                         Cetyl Alcohol 1.000                                                           Stearyl Alcohol 0.500                                                         Soybean Oil 0.460                                                             BHT 0.100                                                                     Vitamin E Acetate 0.100                                                       Lauroyl Lysine 0.500                                                        ______________________________________                                    

This formulation had an alcoholic odor and was somewhat wet inspreadingupon application to the skin. It demonstrated that the level ofalcohol should be about 15 weight percent or below in order to achievean esthetic formulation.

EXAMPLE 23

A formulation was prepared having about 7 weight percent of lauroyllysine, as follows:

    ______________________________________                                        Component CTFA Name                                                                             % (w/w)                                                     ______________________________________                                        Deionized Water   63.275                                                        Glycerin 5.000                                                                Panthenol 0.500                                                               Allantoin 0.150                                                               Carbomer 0.300                                                                Disodium EDTA 0.200                                                           Sodium Hydroxide 0.135                                                        Alcohol 2.780                                                                 Phenoxyethanol 0.700                                                          Methylparaben 0.230                                                           Propylparaben 0.070                                                           Glyceryl Stearate & 5.000                                                     PEG 100 Stearate                                                              Octylmethoxy- 6.000                                                           cinnamate                                                                     C12-15 Alkyl 4.000                                                            Benzoate                                                                      White Petrolatum 1.500                                                        Cetyl Palmitate 1.000                                                         Cetyl Alcohol 1.000                                                           Stearyl Alcohol 0.500                                                         Soybean Oil 0.460                                                             BHT 0.100                                                                     Vitamin E Acetate 0.100                                                       Lauroyl Lysine 7.000                                                        ______________________________________                                    

This product was esthetically satisfactory, however, additional amountsof lauroyl lysine would most probably not provide additional estheticbenefit and may produce pastiness in the emulsion.

EXAMPLE 24

Several formulations were prepared to demonstrate the necessity ofbalancing the dry, emollient oil portion of the oil phase with thesubstantive oil or wax portion of the oil phase in order to achieve anesthetic formulation. Composition 24A contained neither dry, emollientoil nor substantive oil or wax. Composition 24B contained only asubstantive oil or wax, octyl hydroxystearate. Composition 24C containeda dry emollient oil, C12-15 alkyl benzoate. Composition 24D containedboth hydroxystearate and C12-15 alkyl benzoate. The compositions were asfollows:

    ______________________________________                                                      24A     24B       24C   24D                                     ______________________________________                                        Deionized Water                                                                             89.498  88.498    85.498                                                                              84.498                                    Carbomer 0.350 0.350 0.350 0.350                                              Disodium EDTA 0.100 0.100 0.100 0.100                                         Panthenol 0.500 0.500 0.500 0.500                                             Glycerin 3.000 3.000 3.000 3.000                                              C12-15 Alkyl Benzoate --  --  4.000 4.000                                     Octyl hydroxystearate -- 1.000 --  1.000                                      Dimethicone 1.000 1.000 1.000 1.000                                           Cetyl Alcohol 2.500 2.500 2.500 2.500                                         Cetearyl alcohol and 1.400 1.400 1.400 1.400                                  Cetearyl glucoside                                                            BHT 0.100 0.100 0.100 0.100                                                   Vitamin E Acetate 0.500 0.500 0.500 0.500                                     Propoylparaben 0.100 0.100 0.100 0.100                                        Triethanolamine 0.400 0.400 0.400 0.400                                       Tocopherol 0.050 0.050 0.050 0.050                                            Polysorbate 20 0.102 0.102 0.102 0.102                                        Paraben Blend 0.400 0.400 0.400 0.400                                       ______________________________________                                    

It was found that compositions 24A was quite grainy in appearance anddry when applied to the skin. It did not provide for sufficient time tospread over the skin upon application as it dried immediately and wouldnot be an acceptable skin care product. Composition 24B, which had nodry emollient oil was not easy to spread, leaving a heavy coated feelingon the skin. Composition 24C, which contained a dry emollient oil but nosubstantive oil or wax had a poor afterfeel as it dried too fast,lacking a feeling of substantive benefit, although it was easily spreadover the skin. Composition 24D had both types of oil and exhibited agood balance of spreadability, absorbability and afterfeel.

EXAMPLE 25

Compositions were made which incorporated a high percentage of dryemollient oil and a high percentage of substantive oil, respectively, asfollows:

    ______________________________________                                        Ingredient         25A     25B                                                ______________________________________                                        Deionized Water    76.498  73.498                                               Carbomer 0.350 0.350                                                          Disodium EDTA 0.100 0.100                                                     Panthenol 0.500 0.500                                                         Glycerin 3.000 3.000                                                          C12-15 Alkyl Benzoate 12.000 4.000                                            Octyl Hydroxystearate 1.000 12.000                                            Dimethicone 1.000 1.000                                                       Cetyl Alcohol 2.500 2.500                                                     Cetearyl Alcohol and 1.400 1.400                                              Cetearyl Glucoside                                                            BHT 0.100 0.100                                                               Vitamin E Acetate 0.500 0.500                                                 Propylparaben 0.100 0.100                                                     Triethanolamine 0.400 0.400                                                   Tocopherol 0.050 0.050                                                        Polysorbate 20 0.102 0.102                                                    Paraben Blend 0.400 0.102                                                   ______________________________________                                    

It was found that composition 25A, containing 12% C12-15 alkyl benzoate,had a greasy feeling, while composition 25B, containing 12% octylhydroxystearate, had a "draggy" afterfeel and left a heavy residue.

EXAMPLE 26

A composition according to this invention may be made containing one ormore vitamins, an antioxidant material, a sunscreen and asoothing/protectant compound as follows:

    ______________________________________                                        Component CTFA Name                                                                              % (w/w)                                                    ______________________________________                                        Deionized Water    69.775                                                       Glycerin 5.000                                                                Panthenol 0.500                                                               Allantoin 0.150                                                               Carbomer 0.300                                                                Disodium EDTA 0.200                                                           Sodium Hydroxide 0.135                                                        Alcohol 2.780                                                                 Phenoxyethanol 0.700                                                          Methylparaben 0.230                                                           Propylparaben 0.070                                                           Glyceryl Stearate & 5.000                                                     PEG 100 Stearate                                                              Octylmethoxycinnamate 6.000                                                   C12-15 Alkyl Benzoate 4.000                                                   White Petrolatum 1.500                                                        Cetyl Palmitate 1.000                                                         Cetyl Alcohol 1.000                                                           Stearyl Alcohol 0.500                                                         Soybean Oil 0.460                                                             BHT 0.100                                                                     Vitamin E Acetate 0.100                                                       Lauroyl Lysine 0.500                                                        ______________________________________                                    

EXAMPLE 27

A composition according to this invention may be made containingantiinflammatory compounds, including a steroidal compound, anon-steroidal compound and/or a naturally derived antiinflammatorycompound, as follows:

    ______________________________________                                        Component CTFA Name                                                                              % (w/w)                                                    ______________________________________                                        Composition 27A:                                                                Deionized Water 72.498                                                        Carbomer 0.350                                                                Disodium EDTA 0.100                                                           Panthenol 0.500                                                               Glycerin 3.000                                                                C12-15 Alkyl Benzoate 4.000                                                   Octyl Hydroxystearate 12.000                                                  Hydrocortisone 1.000                                                          and its respective salts                                                      Dimethicone 1.000                                                             Cetyl Alcohol 2.500                                                           Cetearyl Alcohol and 1.400                                                    Cetearyl Glucoside                                                            BHT 0.100                                                                     Vitamin E Acetate 0.500                                                       Propylparaben 0.100                                                           Triethanolamine 0.400                                                         Tocopherol 0.050                                                              Polysorbate 20 0.102                                                          Paraben Blend 0.400                                                           Composition 27B:                                                              Deionized Water 71.498                                                        Carbomer 0.350                                                                Disodium EDTA 0.100                                                           Panthenol 0.500                                                               Glycerin 3.000                                                                C12-15 Alkyl Benzoate 4.000                                                   Octyl Hydroxystearate 12.000                                                  Ibuprofen 2.000                                                               Dimethicone 1.000                                                             Cetyl Alcohol 2.500                                                           Cetearyl Alcohol and 1.400                                                    Cetearyl Glucoside                                                            BHT 0.100                                                                     Vitamin E Acetate 0.500                                                       Propylparaben 0.100                                                           Triethanolamine 0.400                                                         Tocopherol 0.050                                                              Polysorbate 20 0.102                                                          Paraben Blend 0.400                                                           Composition 27C:                                                              Deionized Water 70.298                                                        Japanese Green Tea Extract 1.000                                              Carbomer 0.350                                                                Disodium EDTA 0.100                                                           Panthenol 0.500                                                               Glycerin 3.000                                                                C12-15 Alkyl Benzoate 4.000                                                   Octyl Hydroxystearate 12.000                                                  Glycyrrhizic acid 1.000                                                       Stearyl Glycyrrhetinate 1.000                                                 Bisabolol 0.200                                                               Dimethicone 1.000                                                             Cetyl Alcohol 2.500                                                           Cetearyl Alcohol and 1.400                                                    Cetearyl Glucoside                                                            BHT 0.100                                                                     Vitamin E Acetate 0.500                                                       Propylparaben 0.100                                                           Triethanolamine 0.400                                                         Tocopherol 0.050                                                              Polysorbate 20 0.102                                                          Paraben Blend 0.400                                                         ______________________________________                                    

EXAMPLE 27

A composition according to this invention may be made which containsoil-soluble vitamins in combination with vitamin A palmitate, asfollows:

    ______________________________________                                        Component CTFA Name                                                                              % (w/w)                                                    ______________________________________                                        Deionized Water    83.498                                                       Carbomer 0.350                                                                Disodium EDTA 0.100                                                           Panthenol 0.500                                                               Glycerin 3.000                                                                C12-15 Alkyl Benzoate 4.000                                                   Octyl Hydroxystearate 1.000                                                   Dimethicone 1.000                                                             Cetyl Alcohol 2.500                                                           Cetearyl Alcohol and 1.400                                                    Cetearyl Gluoside                                                             BHT 0.100                                                                     Vitamin E Acetate 0.500                                                       Propylparaben 0.100                                                           Triethanolamine 0.400                                                         Tocopherol 0.050                                                              Vitamin A Alcohol 0.102                                                       Vitamin A Palmitate 1.000                                                     Paraben Blend 0.400                                                         ______________________________________                                    

EXAMPLE 28

A composition in accordance with this invention may be made whichcontains proteins and/or amino acids, as follows:

    ______________________________________                                        Component CTFA Name                                                                              % (w/w)                                                    ______________________________________                                        Deionized Water    69.075                                                       Glycerin 5.000                                                                Panthenol 0.500                                                               Allantoin 0.150                                                               Sodium Hyaluronate 0.200                                                      Carbomer 0.300                                                                Disodium EDTA 0.200                                                           Sodium Hydroxide 0.135                                                        Alcohol 2.780                                                                 Phenoxyethanol 0.700                                                          Methylparaben 0.230                                                           Propylparaben 0.070                                                           Glyceryl Stearate & 5.000                                                     PEG 100 Stearate                                                              Octylmethoxycinnamate 6.000                                                   Hydrolyzed Collagen 0.500                                                     C12-15 Alkyl Benzoate 4.000                                                   White Petrolatum 1.500                                                        Cetyl Palmitate 1.000                                                         Cetyl Alcohol 1.000                                                           Stearyl Alcohol 0.500                                                         Soybean Oil 0.460                                                             BHT 0.100                                                                     Vitamin E Acetate 0.100                                                       Lauroyl Lysine 0.500                                                        ______________________________________                                    

EXAMPLE 29

A composition in accordance with this invention may be made whichincorporates natural extracts, such as saponins, flavonoids, tannins andthe like, as follows:

    ______________________________________                                        Component CTFA Name                                                                              % (w/w)                                                    ______________________________________                                        Deionized Water    67.775                                                       Glycerin 5.000                                                                Witch Hazel Extract 1.000                                                     Panthenol 0.500                                                               Allantoin 0.150                                                               Fagus Silvatica Extract 0.500                                                 Carbomer 0.300                                                                Disodium EDTA 0.200                                                           Sodium Hydroxide 0.135                                                        Alcohol 2.780                                                                 Phenoxyethanol 0.700                                                          Methylparahen 0.230                                                           Propylparahen 0.070                                                           Glyceryl Stearate & 5.000                                                     PEG 100 Stearate                                                              Octylmethoxycinnamate 6.000                                                   Pilewort Extract 0.500                                                        C12-15 Alkyl Benzoate 4.000                                                   White Petrolatum 1.500                                                        Cetyl Palmitate 1.000                                                         Cetyl Alcohol 1.000                                                           Stearyl Alcohol 0.500                                                         Soybean Oil 0.460                                                             BHT 0.100                                                                     Vitamin E Acetate 0.100                                                       Lauroyl Lysine 0.500                                                        ______________________________________                                    

EXAMPLE 30

A composition was made which contains a retinol compound anddepigmentation materials which is effective in producing even skincolor, as follows:

    ______________________________________                                        Ingredient         w/w %                                                      ______________________________________                                        Deionized water    74.6102                                                      Hydroxyethylcellulose 1.00                                                    Xanthan Gum 0.20                                                              Disodium EDTA 0.10                                                            D Panthenol 0.50                                                              Glcyerin 3.00                                                                 Glutathione 0.20                                                              Magnesium-L-ascorbyl- 3.00                                                    phosphate                                                                     Citric acid 0.05                                                              C12-15 Alkyl benzoate 4.00                                                    Octyl hydroxystearate 1.00                                                    Dimethicone 1.00                                                              Cetyl alcohol 2.50                                                            Cetearyl glucoside 1.40                                                       di-alpha tocopheryl acetate 0.50                                              Octyl methoxycinnamate 4.00                                                   Methyl paraben 0.2%                                                           Propyl paraben 0.0987%                                                        Phenoxyethanol 0.7333%                                                        10% Sodium hydroxide 0.80                                                     di-alpha tocopherol 0.05                                                      Vitamin A/Tween 45% 0.0686                                                    Lecithin 70%                                                                  Ascorbyl palmitate 25%                                                        Alpha tocopherol 5% 0.001                                                     Tea leaf distilled solution 1.00                                            ______________________________________                                    

What is claimed is:
 1. A topical oil-in-water emulsion compositioncomprising:a) an emulsifier system selected from the group consistingof:i) a mixture of glyceryl stearate and polyethylene glycol 100stearate; ii) cetearyl alcohol and cetearyl glucoside; iii) a mixture ofa polyethylene glycol ether of stearyl alcohol of the formula:

    CH.sub.3 (CH.sub.2).sub.10 CH.sub.2 (OCH.sub.2 CH.sub.2).sub.n OH

Wherein n is 21 and a polyethylene glycol ether of stearyl alcohol ofthe formula:

    CH.sub.3 (CH.sub.2).sub.16 CH.sub.2 (OCH.sub.2 CH.sub.2).sub.n OH

Wherein n is 2; and iv) a mixture of sorbitan stearate and polysorbate60 (a mixture of stearate esters of sorbitol and sorbitol anhydridescondensed with 20 moles of ethylene oxide); b) a co-emulsifier selectedfrom the group consisting of: cetyl alcohol, stearyl alcohol andmixtures thereof; c) an oil phase present in the amount of from about 2to about 20 percent by weight of the total emulsion compositioncomprising:i) a light, dry absorbable oil and ii) substantive, emollientoils or waxeswherein said light dry absorbable oil and said substantiveoil or wax are present in a ratio of from about 1:3 to about 10:1; d) aretinoid;said composition having a pH of from about 4 to about
 10. 2. Acomposition according to claim 1 wherein said emulsifier systemcomprises a mixture of glycerylstearate and polyethylene glycol 100stearate.
 3. A composition according to claim 1 wherein said emulsifiersystem comprises cetearyl glucoside.
 4. A composition according to claim1 wherein said emulsifier system comprises a mixture of a polyethyleneglycol ether of stearyl alcohol of the formula:

    CH.sub.3 (CH.sub.2).sub.16 CH.sub.2 (OCH.sub.2 CH.sub.2).sub.n OH

wherein n is 21 and a polyethylene glycol ether of stearyl alcohol ofthe formula:

    CH.sub.3 (CH.sub.2).sub.16 CH.sub.2 (OCH.sub.2 CH.sub.2).sub.n OH

wherein n is
 2. 5. A composition according to claim 1 wherein saidemulsifier system comprises a mixture of sorbitan stearate andpolysorbate 60 (a mixture of stearate esters of sorbitol and sorbitolanhydrides condensed with 20 moles of ethylene oxide).
 6. A compositionaccording to claim 1 wherein said co-emulsifier is cetyl alcohol.
 7. Acomposition according to claim 1 wherein said co-emulsifier is stearylalcohol.
 8. A composition according to claim 1 wherein saidco-emulsifier is a mixture of cetyl alcohol and stearyl alcohol.
 9. Acomposition according to claim 1 wherein said light, dry absorbable oilis selected from the group consisting of C12-15 alkyl benzoic acid esterand capric caprylic triglyceride and a mixture thereof.
 10. Acomposition according to claim 9 wherein said light, dry absorbable oilis C12-15 alkyl benzoic acid ester.
 11. A composition according to claim9 wherein said light, dry absorbable oil is present in an amount of fromabout 2 to about 15 percent by weight of the composition.
 12. Acomposition according to claim 1 wherein said substantive, emollient oilor wax is selected from the group consisting of petrolatum, cetylpalmitate, octyl hydroxy stearate, silicone oil and mixtures thereof.13. A composition according to claim 12 wherein said substantive,emollient oil or wax is present in an amount of from about 1 to about 12percent by weight of the composition.
 14. A composition according toclaim 1 wherein said light, dry absorbable oil and said substantive,emollient oil or wax are present in the composition in a ratio of fromabout 1:3 to about 10:1.
 15. A composition according to claim 14 whereinsaid light, dry absorbable oil and said substantive, emollient oil orwax are present in the composition in a ratio of from about 2:1 to about1:1.
 16. A composition according to claim 3 wherein said co-emulsifieris cetyl alcohol.
 17. A composition according to claim 3 wherein saidco-emulsifier is a mixture of cetyl alcohol and stearyl alcohol.
 18. Acomposition according to claim 1 wherein said composition furthercomprises a lower alkyl alcohol.
 19. A composition according to claim 18wherein said lower alkyl alcohol is ethyl alcohol.
 20. A compositionaccording to claim 1 wherein said composition further comprises adetackifying compound.
 21. A composition according to claim 20 whereinsaid detackifying compound is selected from the group consisting oflauroyl lysine, talc, boron nitride, and mica.
 22. A compositionaccording to claim 21 wherein said detackifying compound is lauroyllysine.
 23. A composition according to claim 1 wherein said compositionfurther comprises an irritation mitigation component selected from thegroup consisting of octyl methoxy cinnamate, homosalate, menthylanthranilate, octocrylene, octyl dimethyl PABA, octyl salicylate, TEAsalicylate and ethyl dihydroxypropyl PABA and DEA methoxy cinnamate. 24.A composition according to claim 3 wherein said co-emulsifier is cetylalcohol.
 25. A skin care composition according to claim 1 wherein saidcomposition further comprises an imidazole compound.
 26. A skin carecomposition according to claim 25 wherein said azole compound is animidazole compound.
 27. A skin care composition according to claim 26wherein said imidazole compound is selected from the group consisting ofitraconazole, ketoconazole or miconazole.
 28. A skin care compositionaccording to claim 1 wherein said composition further comprises acorticosteroid.
 29. A skin care composition according to claim 28wherein said corticosteroid is hydrocortisone.
 30. A skin carecomposition according to claim 1 wherein said composition furthercomprises a depigmentation agent.
 31. A skin care composition accordingto claim 30 wherein said depigmentation agent is selected from the groupconsisting of licorice extract, hydroquinone, kojic acid, gatuline A,micromerol, glutathione, magnesium-L-ascorbyl-2-phosphate, arbutin,placenta extract and mixtures thereof.
 32. A skin care compositionaccording to claim 1 wherein said composition further comprises asunscreen agent.
 33. A skin care composition according to claim 32wherein said sunscreen agent is octylmethoxycinnamate.
 34. A skin carecomposition according to claim 33 wherein said sunscreen agent isselected from the group consisting of zinc oxide, titanium dioxide andmixtures thereof.
 35. A skin care composition according to claim 1wherein said composition further comprises an anti-oxidant.
 36. A skincare composition according to claim 35 wherein said anti-oxidant isselected from the group consisting of ascorbic acid, vitamin B, biotin,pantothenic acid, vitamin D, and vitamin E.
 37. A container for a skincare composition according to claim 1 characterized in that saidcomposition is stored in a container in which said composition is out ofcontact with oxygen.